Chemical compounds

ABSTRACT

The invention provides compounds of formula (I): 
                         
wherein: X is CH 2 , O, S(O) 2  or NR 10 ; Y is a bond, CH 2 , NR 35 , CH 2 NH, CH 2 NHC(O), CH(OH), CH(NHCOR 33 ), CH(NHSO 2 R 34 ), CH 2 O or CH 2 S; Z is C(O), or when Y is a bond Z can also be S(O) 2 ; R 1  is optionally substituted aryl, optionally substituted heterocyclyl or C 4-6  cycloalkyl fused to a benzene ring; and R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8 , R 9 , R 10 , R 32 , R 33 , R 34  and R 35  are as defined herein; are modulators of chemokine (especially CCR3) activity (for use in, for example, treating asthma). The invention also provides a process for making 4-(3,4-dichlorophenoxy)piperidine, which is useful as an intermediate for making certain compounds of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the national phase application under 35 U.S.C. §371of PCT International Application No. PCT/SE03/00258, filed Feb. 17,2003, which claims priority to Swedish Application Serial No. 0200465-3,filed Feb. 18, 2002 and Swedish Application Serial No. 0202673-0, filedSep. 9, 2002.

The present invention concerns piperidine derivatives havingpharmaceutical activity, to processes for preparing such derivatives, topharmaceutical compositions comprising such derivatives and to the useof such derivatives as active therapeutic agents. The invention alsoprovides a process for making 4-(3,4-dichlorophenoxy)piperidine, whichis useful as an intermediate for making certain compounds of theinvention.

Pharmaceutically active piperidine derivatives are disclosed in WO01/62728, WO 01/62729 and WO 01/62757.

Chemokines are chemotactic cytokines that are released by a wide varietyof cells to attract-macrophages, T cells, eosinophils, basophils andneutrophils to sites of inflammation and also play a rôle in thematuration of cells of the immune system. Chemokines play an importantrôle in immune and inflammatory responses in various diseases anddisorders, including asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. Thesesmall secreted molecules are a growing superfamily of 8-14 kDa proteinscharacterised by a conserved four cysteine motif. The chemokinesuperfamily can be divided into two main groups exhibitingcharacteristic structural motifs, the Cys-X-Cys (C-X-C, or α) andCys-Cys (C-C, or β) families. These are distinguished on the basis of asingle amino acid insertion between the NH-proximal pair of cysteineresidues and sequence similarity.

The C-X-C chemokines include several potent chemoattractants andactivators of neutrophils such as interleukin-8 (IL-8) andneutrophil-activating peptide 2 (NAP-2).

The C-C chemokines include potent chemoattractants of monocytes andlymphocytes, but not neutrophils, such as human monocyte chemotacticproteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation,Normal T Expressed and Secreted), eotaxins and the macrophageinflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. Thesereceptors represent good targets for drug development since agents whichmodulate these receptors would be useful in the treatment of disordersand diseases such as those mentioned above.

Histamine is a basic amine, 2-(4-imidazolyl)-ethylamine, and is formedfrom histidine by histidine decarboxylase. It is found in most tissuesof the body, but is present in high concentrations in the lung, skin andin the gastrointestinal tract. At the cellular level inflammatory cellssuch as mast cells and basophils store large amounts of histamine. It isrecognised that the degranulation of mast cells and basophils and thesubsequent release of histamine is a fundamental mechanism responsiblefor the clinical manifestation of an allergic process. Histamineproduces its actions by an effect on specific histamine G-proteincoupled receptors, which are of three main types, H1, H2 and H3.Histamine H1 antagonists comprise the largest class of medications usedin the treatment of patients with allergic disorders, especiallyrhinitis and urticaria Antagonists of H1 are useful in controlling theallergic response by for example blocking the action of histamine onpost-capillary venule smooth muscle, resulting in decreased vascularpermeability, exudation and oedema. The antagonists also produceblockade of the actions of histamine on the H1 receptors on c-typenociceptive nerve fibres, resulting in decreased itching and sneezing.

Viral infections are known to cause lung inflammation. It has been shownexperimentally that the common cold increases mucosal output of eotaxinin the airways. Instillation of eotaxin into the nose can mimic some ofthe signs and symptoms of a common cold. (See, Greiff L et al Allergy(1999) 54(11) 1204-8 [Experimental common cold increase mucosal outputof eotaxin in atopic individuals] and Kawaguchi M et al Int. Arch.Allergy Immunol. (2000) 122 S1 44 [Expression of eotaxin by normalairway epithelial cells after virus A infection].)

The present invention provides a compound of formula (I):

wherein:

-   X is CH₂, O, S(O)₂ or NR¹⁰;-   Y is a bond, CH₂, NR³⁵, CH₂NH, CH₂NHC(O), CH(OH), CH(NHC(O)R³³),-   CH(NHS(O)₂R³⁴), CH₂O or CH₂S;-   Z is C(O), or when Y is a bond Z can also be S(O)₂;-   R¹ is optionally substituted aryl, optionally substituted    heterocyclyl or C₄₋₆ cycloalkyl fused to a benzene ring;-   R⁴ is hydrogen, C₁₋₆ alkyl (optionally substituted by C₃₋₆    cycloalkyl) or C₃₋₆ cycloalkyl;-   R², R³, R⁵, R⁶, R⁷ and R⁸ are, independently, hydrogen, C₁₋₆ alkyl    or C₃₋₆ cycloalkyl;-   m and n are, independently, 0 or 1;-   R⁹ is optionally substituted aryl or optionally substituted    heterocyclyl;-   R¹⁰, R³² and R³⁵ are, independently, hydrogen, C₁₋₆ alkyl or C₃₋₆    cycloalkyl;-   R³³ and R³⁴ are C₁₋₆ alkyl or C₃₋₆ cycloalkyl;    wherein the foregoing aryl and heterocyclyl moieties are, where    possible, optionally substituted by: halogen, cyano, nitro, hydroxy,    oxo, S(O)_(k)R¹², OC(O)NR¹³R¹⁴, NR¹⁵R¹⁶, NR¹⁷C(O)R¹⁸,    NR¹⁹C(O)NR²⁰R²¹, S(O)₂NR²²R²³, NR²⁴S(O)₂R²⁵, C(O)NR²⁶R²⁷, C(O)R²⁸,    CO₂R²⁹, NR³⁰CO₂R³¹, C₁₋₆ alkyl (itself optionally mono-substituted    by NHC(O)phenyl), C₁₋₆ haloalkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₁₋₆    alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkoxy(C₁₋₆)alkoxy, C₁₋₆ alkylthio,    C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, methylenedioxy,    difluoromethylenedioxy, phenyl, phenyl(C₁₋₄)alkyl, phenoxy,    phenylthio, phenyl(C₁₋₄)alkoxy, morpholinyl, heteroaryl,    heteroaryl(C₁₋₄)alkyl, heteroaryloxy or heteroaryl(C₁₋₄)alkoxy,    wherein any of the immediately foregoing phenyl and heteroaryl    moieties are optionally substituted with halogen, hydroxy, nitro,    S(O)_(r)(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄    alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄    alkyl), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄    alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃;-   k and r are, independently, 0, 1 or 2;-   R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁶,    R²⁷, R²⁹ and R³⁰ are, independently, hydrogen, C₁₋₆ alkyl    (optionally substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl),    CH₂(C₂₋₆ alkenyl), C₃₋₆ cycloalkyl, phenyl (itself optionally    substituted by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), NH(C₁₋₄    alkyl)₂, S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),    S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl, C(O)NH₂, C(O)NH(C₁₋₄ alkyl),    C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl),    NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃) or heterocyclyl    (itself optionally substituted by halogen, hydroxy, nitro, NH₂,    NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂,    S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄    alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl, CO₂H,    CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄    alkyl), CF₃ or OCF₃); alternatively NR¹³R¹⁴, NR¹⁵R¹⁶, NR²⁰R²¹,    NR²²R²³, NR²⁶R²⁷, may, independently, form a 4-7 membered    heterocyclic ring selected from the group: azetidine (itself    optionally substituted by hydroxy or C₁₋₄ alkyl), pyrrolidine,    piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter    optionally substituted by C₁₋₄ alkyl on the distal nitrogen; R¹²,    R²⁵, R²⁸ and R³¹ are, independently, C₁₋₆ alkyl (optionally    substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl), CH₂(C₂₋₄    alkenyl), phenyl (itself optionally substituted by halogen, hydroxy,    nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and these alkyl groups    may join to form a ring as described for R¹³ and R¹⁴ above),    S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄    alkyl)₂ (and these alkyl groups may join to form a ring as described    for R¹³ and R¹⁴ above), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,    C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl groups may    join to form a ring as described for R¹³ and R¹⁴ above), CO₂H,    CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄    alkyl), CF₃ or OCF₃) or heterocyclyl (itself optionally substituted    by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and    these alkyl groups may join to form a ring as described for R¹³ and    R¹⁴ above), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),    S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form a ring    as described for R¹³ and R¹⁴ above), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy,    C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl    groups may join to form a ring as described for R¹³ and R¹⁴ above),    CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl),    C(O)(C₁₋₄ alkyl), CF₃ or OCF₃);    provided that when X is CH₂ and m and n are both 0 then Y is not    NR³⁵;    or an N-oxide thereof, or a pharmaceutically acceptable salt,    solvate or solvate of a salt thereof.

Certain compounds of the present invention can exist in differentisomeric forms (such as enantiomers, diastereomers, geometric isomers ortautomers). The present invention covers all such isomers and mixturesthereof in all proportions.

Suitable salts include acid addition salts such as a hydrochloride,dihydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate,fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate orp-toluenesulfonate.

The compounds of the invention may exist as solvates (such as hydrates)and the present invention covers all such solvates.

Halogen includes fluorine, chlorine, bromine and iodine.

Alkyl groups and moieties are straight or branched chain and are, forexample, methyl, ethyl, n-propyl, iso-propyl or tert-butyl. Alkyl groupspreferably comprise 1-6 carbon atoms.

Alkenyl is, for example, vinyl or allyl. Alkenyl groups preferablycomprise 2-6 carbon atoms.

Alkynyl is, for example, propargyl. Alkynyl groups preferably comprise2-6 carbon atoms.

Cycloalkyl is monocyclic and is, for example, cyclopropyl, cyclopentylor cyclohexyl. Cycloalkyl groups preferably comprise 3-6 carbon atoms.

Cycloalkyl fused to a benzene ring is, for example,bicyclo[4.2.0]octa-1,3,5-trienyl.

Aryl is preferably phenyl or naphthyl.

Heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring,optionally fused to one or more other rings, comprising at least oneheteroatom selected from the group comprising nitrogen, oxygen andsulfur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof.Heterocyclyl is; for example, furyl, thienyl (also known as thiophenyl),pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl,isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl,1,6-dihydropyridinyl (for example in a 6-oxo-1,6-dihydropyridinylmoiety), pyrimidinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (alsoknown as benzfuryl), benz[b]thienyl (also known as benzthienyl orbenzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example in a1,1-dioxo-2,3-dihydrobenz[b]thienyl moiety), indazolyl, benzimidazolyl,bentriazolyl, benzoxazolyl benzthiazolyl, 1,2-dihydrobenzthiazolyl (forexample in a 1H-benzthiazol-2-one-yl moiety), 2,3-dihydrobenzthiazolyl(for example in a 2,3-dihydrobenzthiazol-2-one-yl moiety),1,2,3-benzothiadiazolyl, an imidazopyridinyl (such asimidazo[1,2-a]pyridinyl), thieno[3,2-b]pyridin-6-yl,1,2,3-benzoxadiazolyl (also known as benzo[1,2,3]thiadiazolyl),2,1,3-benzothiadiazolyl, benzofurazan (also known as2,1,3-benzoxadiazolyl), quinoxalinyl, 3,4-dihydro-1H-2,1-benzothiazinyl(for example in a 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl moiety), apyrazolopyridine (for example 1H-pyrazolo[3,4-b]pyridinyl), a purine,3,7-dihydro-purinyl (for example in a 3,7-dihydro-purinyl (for examplein a 3,7-dihydro-purin-2,6-dione-8-yl moiety), quinolinyl,isoquinolinyl, 1,2-dihydroisoquinolinyl (for example in a2H-isoquinolin-1-one-yl (alternatively called1-oxo-1,2-dihydroisoquinolinyl or 1,2-dihydroisoquinolinyl-1-one)moiety), a naphthyridinyl (for example [1,6]naphthyridinyl or[1,8]naphthyridinyl), 1,4-dihydro[1,8]naphthyridinyl (for example in a1H-[1,8]naphthyridin-4-one-yl moiety), or a benzothiazinyl,4H-benzo[1,4]thiazinyl (for example in a 4H-benzo[1,4]thiazin-3-one-ylmoiety); or an N-oxide thereof (such as a pyridine N-oxide), or anS-oxide or S-dioxide thereof. 1,2-Dihydropyridinyl (an alternativenumbering for a 1,6-dihydropyridinyl) can also be present in a2-oxo-1,2-dihydropyridinyl moiety; and 2,3-dihydro-1H-indazolyl can alsobe present in a 3-oxo-2,3-dihydro-1H-indazolyl moiety.

Heterocyclyl also includes cinnolinyl, phthalazinyl,3,4-dihydrophthalazinyl (for example in a 4-oxo-3,4-dihydrophthalazinylmoiety), benzoxazinyl, 2,3-dihydro-4H-1,4-benzoxazinyl (for example in a3-oxo-2,3-dihydro-4H-1,4-benzoxazinyl moiety),3,4-dihydro-2H-1,4-benzoxazinyl (for example in a3-oxo-3,4-dihydro-2H-1,4-benzoxazinyl moiety), isoindolyl,1,3-dihydro-2H-isoindolyl (for example in a1,3-dioxo-1,3-dihydro-2H-isoindolyl moiety), pyrazolotriazinyl (forexample pyrazolo[5,1-c][1,2,4]triazinyl), pyrazinyl, pyridazinyl,9H-purinyl, pyrazolopyriminyl (for example pyrazolo[1,5-a]pyrimidinyl),imidazobenzothiazolyl (for example imidazo[2,1-b][1,3]benzothiazolyl),1,2,5-oxadiazolyl, imidazopyrimidinyl (for exampleimidazo[1,2-a]pyrimidinyl), quinolinyl, 1,2-dihydroquinolinyl (forexample in a 2-oxo-1,2-dihydroquinolinyl moiety) or2,1,3-benzoxadiazolyl (for example as a 1-oxide); or it may additionallybe an N-oxide thereof, or an S-oxide or S-dioxide thereof. Furtherexamples of heterocyclyl are 1,3-benzothiazole,2,3-dihydro-1,3-benzothiazole (for example in a2-oxo-2,3-dihydro-1,3-benzothiazole moiety), 4,5,6,7-tetrahydroindazole,2,3-dihydro-1H-benzimidazole (for example in a2-oxo-2,3-dihydro-1H-benzimidazole moiety) and 1,4-dihydroquinoline (forexample in a 4-oxo-1,4-dihydroquinoline moiety).

An N-oxide of a compound of formula (I) or (Ia) is, for example, a1-oxy-piperidinyl compound.

Heteroaryl is an aromatic heterocyclyl. Thus it is, for example furyl,thienyl, pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl,imidazolyl, pyridinyl, pyrimidinyl, indolyl, benzo[b]furyl,benz[b]thienyl, indazolyl, benzimidazolyl, benztriazolyl, benzoxazolyl,benzthiazolyl, 1,2,3-benzothiadiazolyl, an imidazopyridinyl,thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl,2,1,3-benzothiadiazolyl, benzofurazan, quinoxalinyl, a pyrazolopyridine,a purine, quinolinyl, isoquinolinyl, a naphthyridinyl, a benzothiazinyl,cinnolinyl, phthalazinyl, benzoxazinyl, isoindolyl, pyrazolotriazinylpyrazinyl, pyridazinyl, pyrazolopyrimidinyl, imidazobenzothiazolyl,imidazopyrimidinyl quinolinyl or 2,1,3-benzoxadiazolyl; or an N-oxidethereof (such as a pyridine N-oxide), or an S-oxide or S-dioxidethereof.

Haloalkyl is an alkyl group carrying one or more (such as 1 to 6)halogen atoms and is, for example, CF₃. Alkoxyalkyl is, for example,CH₃OCH₂, CH₃CH₂OCH₂ or CH₃CH₂O(CH₂)₂. Haloalkyloxy is an alkoxy groupcarrying one or more (such as 1 to 6) halogen atoms and is, for example,OCF₃. Alkoxyalkoxy is, for example, CH₃OCH₂O, CH₃CH₂OCH₂O orCH₃CH₂O(CH₂)₂O. Phenylalkyl is, for example, benzyl, phenyleth-1-yl orphenyleth-2-yl. Phenylalkoxy is, for example benzyloxy. Heteroarylalkylis, for example, pyridinylmethyl or pyrimidinylmethyl. Heteroaryloxy is,for example, pyridinyloxy or pyrimidinyloxy. Heteroarylalkoxy is, forexample, pyridinylmethoxy or pyrimidinylmethoxy.

In one aspect the present invention provides a compound of formula (I)wherein: X is CH₂, O, S(O)₂ or NR¹⁰; Y is a bond, CH₂, NR³⁵, CH₂NH,CH₂NHC(O), CH(OH), CH(NHC(O)R³³), CH(NHS(O)₂R³⁴), CH₂O or CH₂S; Z isC(O), or when Y is a bond Z can also be S(O)₂; R¹ is optionallysubstituted aryl, optionally substituted heterocyclyl or C₄₋₆-cycloalkylfused to a benzene ring; R⁴ is hydrogen, C₁₋₆ alkyl (optionallysubstituted by C₃₋₆ cycloalkyl) or C₃₋₆ cycloalkyl; R², R³, R⁵, R⁶, R⁷and R⁸ are, independently, hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; mand n are, independently, 0 or 1; R⁹ is optionally substituted aryl oroptionally substituted heterocyclyl; R¹⁰, R³², R³³ and R³⁵ are,independently, hydrogen or C₁₋₆ alkyl, R³⁴ is C₁₋₆ alkyl; wherein theforegoing aryl and heterocyclyl moieties are, where possible, optionallysubstituted by halogen, cyano, nitro, hydroxy, oxo, S(O)_(k)R¹²,OC(O)NR¹³R¹⁴, NR¹⁵R¹⁶, NR¹⁷C(O)R¹⁸, NR¹⁹C(O)NR²⁰R²¹, S(O)₂NR²²R²³,NR²⁴S(O)₂R²⁵, C(O)NR²⁶R²⁷, C(O)R²⁸, CO₂R²⁹, NR³⁰CO₂R³¹, C₁₋₆ alkyl, C₁₋₆alkylthio, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆alkoxy(C₁₋₆)alkoxy, C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl,phenyl(C₁₋₄)alkyl, phenoxy, phenylthio, phenyl(C₁₋₄)alkoxy, heteroaryl,heteroaryl(C₁₋₄)alkyl, heteroaryloxy or heteroaryl(C₁₋₄)alkoxy, whereinany of the immediately foregoing phenyl and heteroaryl moieties areoptionally substituted with halogen, hydroxy, nitro, S(O)_(r)(C₁₋₄alkyl), S(O)₂NH₂, cyano, C₁₋₄ alkyl, C₁₋₆ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄alkyl), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl),C(O)(C₁₋₄ alkyl), CF₃ or OCF₃; k and r are, independently, 0, 1 or 2;R¹³, R¹⁴, R¹⁵R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁶, R²⁷, R²⁹,R³⁰, and R³¹ are, independently, hydrogen, C₁₋₆ alkyl (optionallysubstituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl), CH₂(C₂₋₆ alkenyl),phenyl (itself optionally substituted by halogen, hydroxy, nitro, NH₂,NH(C₁₋₄ alkyl), NH(C₁₋₄ alkyl)₂, S(O)₂(C₁₋₄ alkyl), S(O)₂NH, S(O)₂NH(Calkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄ alkyl),NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃)or heterocyclyl (itself optionally substituted by halogen, hydroxy,nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄alkyl), NHC(O)(C₁₋₄ alkyl NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ orOCF₃); alternatively NR¹³R¹⁴, NR¹⁵R¹⁶, NR²⁰R²¹, NR²²R²³, NR²⁶R²⁷, may,independently, form a 4-7 membered heterocyclic ring, azetidine,pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, thelatter optionally substituted by C₁₋₄ alkyl on the distal nitrogen; R¹²,R²⁵ and R²⁸ are, independently, C₁₋₆ alkyl (optionally substituted byhalogen, hydroxy or C₃₋₁₀ cycloalkyl), CH₂(C₂₋₆ alkenyl), phenyl (itselfoptionally substituted by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl),N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form a ring asdescribed for R¹³ and R¹⁴ above), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups mayjoin to form a ring as described for R¹³ and R¹⁴ above), cyano, C₁₋₄alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (andthese alkyl groups may join to form a ring as described for R¹³ and R¹⁴above), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl),C(O)(C₁₋₄ alkyl), CF₃ or OCF₃) or heterocyclyl (itself optionallysubstituted by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄alkyl)₂ (and these allyl groups may join to form a ring as described forR¹³ and R¹⁴ above), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form a ring asdescribed for R¹³ and R¹⁴ above), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy,C(O)NH₂, C(O)NH(C₁₋₄-alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl groupsmay join to form a ring as described for R¹³ and R¹⁴ above), CO₂H,CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄alkyl), CF₃ or OCF₃); provided that when X is CH₂ and m and n are both 0then Y is not NR³⁵; or an N-oxide thereof; or a pharmaceuticallyacceptable salt, solvate or solvate of a salt thereof.

In another aspect the present invention provides a compound of formula(Ia):

wherein: X is CH₂, O, S(O)₂ or NR¹⁰; R¹ is optionally substituted arylor optionally substituted heterocyclyl; R⁴ is hydrogen, C₁₋₆ alkyl(optionally substituted by C₃₋₆ cycloalkyl) or C₃₋₆ cycloalkyl; R², R³,R⁵, R⁶, R⁷ and R⁸ are, independently, hydrogen, C₁₋₆ alkyl or C₃₋₆cycloalkyl; m and n are, independently, 0 or 1; R⁹ is optionallysubstituted aryl or optionally substituted heterocyclyl; R¹⁰ is hydrogenor C₁₋₆ alkyl; wherein the foregoing aryl and heterocyclyl moieties are,where possible, optionally substituted by: halogen, cyano, nitro,hydroxy, oxo, S(O)_(k)R¹², OC(O)NR¹³R¹⁴, NR¹⁵R¹⁶, NR¹⁷C(O)R¹⁸,NR¹⁹C(O)NR²⁰R²¹, S(O)₂NR²²R²³, NR²⁴S(O)₂R²⁵, C(O)NR²⁶R²⁷, C(O)R²⁸,CO₂R²⁹, NR³⁰CO₂R³¹, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkoxy(C₁₋₆)alkoxy, C₁₋₆ alkylthio,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, methylenedioxy,difluoromethylenedioxy, phenyl, phenyl(C₁₋₄)alkyl, phenoxy, phenylthio,phenyl(C₁₋₄)alkoxy, heteroaryl, heteroaryl(C₁₋₄)alkyl, heteroaryloxy orheteroaryl(C₁₋₄)alkoxy; wherein any of the immediately foregoing phenyland heteroaryl moieties are optionally substituted with halogen,hydroxy, nitro, S(O)_(r)(C₁₋₄ alkyl), S(O)₂NH₂, cyano, C₁₋₄ alkyl, C₁₋₄alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃; k and r are,independently, 0, 1 or 2; R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹,R²², R²³, R²⁴, R²⁶, R²⁷, R²⁹, R³⁰, and R³¹ are, independently, hydrogen,C₁₋₆ alkyl (optionally substituted by halogen, hydroxy or C₃₋₁₀cycloalkyl), CH₂(C₂₋₆ alkenyl), phenyl (itself optionally substituted byhalogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), NH(C₁₋₄ alkyl)₂,S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,C(O)NH(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl),NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃) or heterocyclyl(itself optionally substituted by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, S(O)₂(C₁₋₄ allyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄alkyl), S(O alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄ alkyl),NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃);alternatively NR¹³R¹⁴, NR¹⁵R¹⁶, NR²⁰R²¹, NR²²R²³, NR²⁶R²⁷, mayindependently, form a 4-7 membered heterocyclic ring, azetidine,pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, thelatter optionally substituted by C₁₋₄ alkyl on the distal nitrogen; R¹²,R²⁵ and R²⁸ are, independently, C₁₋₆ allyl (optionally substituted byhalogen, hydroxy or C₃₋₁₀ cycloalkyl), CH₂(C₂₋₆ alkenyl), phenyl (itselfoptionally substituted by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl),N(C₁₋₄ alkyl) (and these alkyl groups may join to form a ring asdescribed for R¹³ and R¹⁴ above), S(O)₂(C₁₋₄ allyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups mayjoin to form a ring as described for R¹³ and R¹⁴ above), cyano, C₁₋₄alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄ alkyl)₂ (andthese alkyl groups may join to form a ring as described for R¹³ and R¹⁴above), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O(C₁₋₄ alkyl),C(O)(C₁₋₄ alkyl), CF₃ or OCF₃) or heterocyclyl (itself optionallysubstituted by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄alkyl)₂ (and these alkyl groups may join to form a ring as described forR¹³ and R¹⁴ above), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),S(O)₂N(C₁₋₁₄ alkyl)₂ (and these alkyl groups may join to form a ring asdescribed for R¹³ and R¹⁴ above), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy,C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl groupsmay join to form a ring as described for R¹³ and R¹⁴ above), CO₂H,CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄alkyl), CF₃ or OCF₃); or an N-oxide thereof; or a pharmaceuticallyacceptable salt, solvate or solvate of a salt thereof.

In a further aspect the present invention provides a compound of formula(I) wherein: X is O; Y is a bond, CH₂, NR³⁵, CH₂NH, CH(OH),CH(NHC(O)R³³), CH(NHS(O)₂R³⁴) or CH₂O; Z is C(O), or when Y is a bond Zcan also be S(O)₂; R¹ is optionally substituted phenyl; R⁴ is hydrogenor C₁₋₆ alkyl; R², R³, R⁵, R⁶, R⁷ and R⁸ are, when present, allhydrogen; m and n are, independently, 0 or 1; R⁹ is optionallysubstituted aryl or optionally substituted heterocyclyl; R³² and R³⁵are, independently, hydrogen or C₁₋₆ alkyl; R³³ and R³⁴ are C₁₋₆ alkyl;wherein the foregoing phenyl, aryl and heterocyclyl moieties are, wherepossible, optionally substituted by: halogen, cyano, hydroxy, oxo,S(O)₂R¹², NR¹⁵R¹⁶, NR¹⁷C(O)R¹⁸, S(O)₂NR²²R²³, NR²⁴S(O)₂R²⁵, C(O)NR²⁶R²⁷,CO₂R²⁹, C₁₋₆ alkyl (itself optionally mono-substituted by NHC(O)phenyl),CF₃, OCF₃, phenyl or heteroaryl; wherein any of the immediatelyforegoing phenyl and heteroaryl moieties are optionally substituted withhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy or CF₃; R¹⁵, R¹⁶, R¹⁷, R¹⁸, R²², R²³,R²⁴, R²⁶, R²⁷ and R²⁹ are, independently, hydrogen, C₁₋₆ alkyl(optionally substituted by hydroxy) or C₃₋₆ cycloalkyl; alternativelyNR²²R²³ may form an azetidine ring (itself optionally substituted byhydroxy or C₁₋₄ alkyl); R¹² and R²⁵ are, independently, C₁₋₆ alkyl orphenyl; or a pharmaceutically acceptable salt thereof.

In a still further aspect R¹ is phenyl optionally substituted (forexample with one, two or three of) by halogen (especially fluoro orchloro), cyano, C₁₋₄ alkyl (especially methyl), C₁₋₄ alkoxy (especiallymethoxy), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂NH(C₃₋₆cycloalkyl), C(O)₂(C₁₋₄ alkyl), C(O)NH(C₁₋₄ alkyl) or C(O)NH₂.

In another aspect R¹ is phenyl optionally substituted (for example withone, two or three of) by halogen (especially fluoro or chloro), cyano,C₁₋₄ alkyl (especially methyl) or C₁₋₄ alkoxy (especially methoxy). In afurther aspect R¹ is phenyl substituted by one, two or three of: fluoro,chloro, methyl or cyano. In another aspect R¹ is phenyl substituted byone, two or three of: fluoro, chloro or methyl. Thus, R¹ is, forexample, 2-methyl-4-chlorophenyl, 3-methyl-2,4-dichlorophenyl,3,4-difluorophenyl, 3-fluoro-4-chlorophenyl or 4-chlorophenyl. In astill further aspect R¹ is 3,4-dichlorophenyl.

In another aspect X is O.

In yet another aspect Y is a bond.

In another aspect Z is C(O).

In a further aspect m is 0.

In a still further aspect n is 0.

In another aspect m and n are both 0.

In another aspect R⁴ is hydrogen or C₁₋₆ alkyl (such as methyl). In yetanother aspect R⁴ is hydrogen.

In yet another aspect R², R³, R⁵, R⁶, R⁷ and R⁸ are all hydrogen; and ina further aspect n is 0, and R², R³, R⁵ and R⁶ are all hydrogen.

In a further aspect R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are, when present, allhydrogen.

In a still further aspect R⁹ is mono- or di-substituted phenyl,unsubstituted heterocyclyl or mono- or di-substituted heterocyclyl, thesubstituents being chosen from those described above.

In another aspect R⁹ is optionally substituted heterocyclyl wherein theheterocyclyl group is: thienyl, pyrrolyl, thiazolyl, pyrazolyl,oxazolyl, isoxazolyl, imidazolyl, 1,2,5-oxadiazolyl, pyridinyl,1,6-dihydropyridinyl (for example in a 6-oxo-1,6-dihydropyridinyl or a2-oxo-1,2-dihydropyridinyl moiety), pyrimidinyl, indolyl, indazolyl,2,3-dihydro-1H-indazolyl (for example in a3-oxo-2,3-dihydro-1H-indazloyl moiety), an imidazopyridinyl (such asimidazo[1,2-a]pyridinyl), 2,1,3-benzothiadiazolyl, quinoxalinyl,quinolinyl, 1,2-dihydroquinolinyl (for example in a2-oxo-1,2-dihydroquinolinyl moiety), 1,4-dihydroquinoline (for examplein a 4-oxo-1,4-dihydroquinoline moiety), isoquinolinyl,1,2-dihydroisoquinolinyl (for example in a 2H-isoquinolin-1-one-yl(alternatively called 1-oxo-1,2-dihydroisoquinolinyl or1,2-dihydroisoquinolinyl-1-one) moiety), cinnolinyl3,4-dihydrophthalazinyl (for example in a 4-oxo-3,4-dihydrophthalazinylmoiety), 2,3-dihydro-4H-1,4-benzoxazinyl (for example in a3-oxo-2,3-dihydro-4H-1,4-benzoxazinyl moiety),3,4-dihydro-2H-1,4-benzoxazinyl (for example in a3-oxo-3,4-dihydro-2H-1,4-benzoxazinyl moiety), 1,3-dihydro-2H-isoindolyl(for example in a 1,3-dioxo-1,3-dihydro-2H-isoindolyl moiety),pyrazolotriazinyl (for example pyrazolo[5,1-c][1,2,4]triazinyl),pyrazolopyrimidinyl (for example pyrazolo[1,5-a]pyrimidinyl),imidazobenzothiazolyl (for example imidazo[2,1-b][1,3]benzothiazolyl),imidazopyrimidinyl (for example imidazo[1,2-a]pyrimidinyl), or2,1,3-benzoxadiazolyl (for example as a 1-oxide), 1,3-benzothiazole,2,3-dihydro-1,3-benzothiazole (for example in a2-oxo-2,3-dihydro-1,3-benzothiazole moiety), 4,5,6,7-tetrahydroindazoleor 2,3-dihydro-1H-benzimidazole (for example in a2-oxo-2,3-dihydro-1H-benzimidazole moiety).

In yet another aspect the aryl (such as phenyl) or heterocyclyl group R⁹is unsubstituted or substituted by one or more of: oxo (where possible),halogen, C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ or OCF₃.

In a further aspect when R⁹ is heterocyclyl it is an optionallysubstituted thienyl, quinolinyl, 1,2-dihydroquinolinyl,1,3-benzthiazolyl, 2,3-dihydro-1,3-benzothiazolylimidazo[1,2-a]pyridinyl, isoquinolinyl or 1,2-dihydroisoquinolinyl; or a1,2-dihydropyridone, a 1,6-dihydropyridone, a pyrazolyl, a pyrrolyl oran indolyl.

In yet another aspect R⁹ is phenyl or heterocyclyl (as defined anywhereabove), either of which is optionally substituted by: halo, hydroxy,nitro, cyano, oxo, amino, C₁₋₄ alkyl (itself optionally substituted byS(O)₂(C₁₋₄ alkyl), or S(O)₂-phenyl), C₁₋₄ alkoxy, S(O)R¹² {wherein k is0, 1 or 2 (preferably 2); and R¹² is C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₃₋₇cycloalkyl(C₁₋₄ alkyl) (such as cyclopropylmethyl) or phenyl}, C(O)NH₂,NHS(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl) or S(O)₂N(C₁₋₄alkyl)₂ (and these alkyl groups may join to form a ring as described forR¹³ and R¹⁴ above).

In another aspect R³² is hydrogen.

In a further aspect R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²²,R²³, R²⁴, R²⁶, R²⁷, R²⁹, R³⁰, and R³¹ are, independently, hydrogen, C₁₋₆alkyl (optionally substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl),CH₂(C₂₋₆ alkenyl), phenyl (itself optionally substituted by halogen orC₁₋₄ alkyl) or heterocyclyl (itself optionally substituted by halogen orC₁₋₄ alkyl); and R¹², R²⁵ and R²⁸ are, independently, C₁₋₆ alkyl(optionally substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl),CH₂(C₂₋₆ alkenyl), phenyl (itself optionally substituted by halogen orC₁₋₄ alkyl) or heterocyclyl (itself optionally substituted by halogen orC₁₋₄ alkyl).

In a still further aspect R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹,R²², R²³, R²⁴, R²⁶, R²⁷, R²⁹ and R³⁰ are, independently, hydrogen, C₁₋₆alkyl (optionally substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl),CH₂(C₂₋₆ alkenyl), phenyl (itself optionally substituted by halogen orC₁₋₄ alkyl) or heterocyclyl (itself optionally substituted by halogen orC₁₋₄ alkyl); and R¹², R²⁵, R²⁸ and R³¹ are, independently, C₁₋₆ alkyl(optionally substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl),CH₂(C₂₋₆ alkenyl), phenyl (itself optionally substituted by halogen orC₁₋₄ alkyl) or heterocyclyl (itself optionally substituted by halogen orC₁₋₄ alkyl).

In yet another aspect R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²²,R²³, R²⁴, R²⁶, R²⁷, R²⁹ and R³⁰ are, independently, hydrogen or C₁₋₆alkyl; and R¹², R²⁵, R²⁸ and R³¹ are, independently, C₁₋₆ alkyl(optionally substituted by hydroxy) or phenyl.

In a further aspect R¹⁰ is hydrogen.

In another aspect R³⁵ is hydrogen or C₁₋₆ alkyl (such as methyl); (forexample R³⁵ is hydrogen).

In yet another aspect R³³ is C₁₋₆ alkyl (such as methyl).

In a further aspect R³⁴ is C₁₋₆ alkyl (such as methyl).

In a still further aspect the present invention provides a compound offormula (I) or (Ia) wherein: R¹ is phenyl optionally substituted by 2halogens (such as chlorine); X is O; m is 0; n is 0 or 1; R², R³, R⁴,R⁵, R⁶, R⁷ and R⁸ are all hydrogen; and R⁹ is phenyl, thienyl,quinolinyl, 1,3-benzthiazolyl, 2,3-dihydro-1,3-benzothiazolyl,imidazo[1,2-a]pyridinyl or 1,2-dihydroisoquinolinyl optionallysubstituted by S(O)₂(C₁₋₄ alkyl) (for example S(O)₂CH₃), halogen (forexample chlorine or fluorine), NH₂, C₁₋₄ alkoxy (such as OCH₃), cyanoor, where possible, oxo.

In another aspect the present invention provides a compound of formula(I) or (Ia) wherein: R¹ is phenyl optionally substituted by 1 or 2halogens (such as chlorine), or by 1 or 2 halogens (such as chlorine)and a C₁₋₄ alkyl (such as methyl); X is O; m is 0; n is 0 or 1; R², R³,R⁴, R⁵ and R⁶ and, when present, R⁷ and R⁸ are all hydrogen; and R⁹ isphenyl, thienyl, quinolinyl, 1,3-benzthiazolyl,2,3-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl,1,2-dihydroisoquinolinyl, 1,2-dihydropyridinyl, 1,6-dihydropyridinyl orpyrazolyl, all optionally substituted by S(O)₂(C₁₋₄ alkyl) (for exampleS(O)₂CH₃), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ (and thetwo alkyl groups may join together to form an azetidine ring), halogen(for example chlorine or fluorine), NH₂, C₁₋₄ alkyl (such as CH₃), C₁₋₄alkoxy (such as OCH₃), CF₃, cyano or, where possible, oxo.

In a further aspect the present invention provides a compound of formula(I) or (Ia) wherein: R¹ is phenyl optionally substituted by 1 or 2halogens (such as chlorine), and optionally substituted by 0 or 1 C₁₋₆alkyl (such as methyl); X is O; m is 0; n is 0 or 1; R², R³, R⁴, R⁵ andR⁶, and, when present, R⁷ and R⁸ are all hydrogen; and R⁹ is phenyl,thienyl, quinolinyl, 1,3-benzthiazolyl, 2,3-dihydro-1,3-benzothiazolyl,imidazo[1,2-a]pyridinyl, 1,2-dihydroisoquinolinyl, 1,2-dihydropyridinyl,1,6-dihydropyridinyl, pyrazolyl, pyrrolyl or indolyl, all of which areoptionally substituted by S(O)₂(C₁₋₄ alkyl) (for example S(O)₂CH₃),S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂, halogen (for examplechlorine or fluorine), NH₂, C₁₋₄ alkoxy (such as OCH₃), C₁₋₄ alkyl (suchas methyl), CF₃, OCF₃, cyano or, where possible, oxo.

In a still further aspect the present invention provides a compound offormula (I) or (Ia) wherein: R¹ is phenyl optionally substituted by 1 or2 halogens (such as chlorine), and optionally substituted by 0 or 1 C₁₋₆alkyl (such as methyl); X is O; m is 0; n is 0 or 1; R², R³, R⁴, R⁵, R⁶,R⁷ and R⁸ are all hydrogen; and R⁹ is phenyl, thienyl, quinolinyl,1,3-benzthiazolyl, 2,3-dihydro-1,3-benzothiazolyl,imidazo[1,2-a]pyridinyl or 1,2-dihydroisoquinolinyl, all of which areoptionally substituted by S(O)₂(C₁₋₄ alkyl) (for example S(O)₂CH₃),halogen (for example chlorine or fluorine), NH₂, C₁₋₄ alkoxy (such asOCH₃), C₁₋₄ alkyl (such as methyl), CF₃, OCF₃, cyano or, where possible,oxo.

In another aspect the present invention provides a compound of formula(I) or (Ia) wherein R⁹ is isoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl,quinolinyl, 2-oxo-1,2-dihydroquinolinyl, 2-oxo-1,2-dihydropyridinyl,6-oxo-1,6-dihydropyridinyl or pyrazolyl; each optionally substituted byhalogen (such as fluorine), C₁₋₄ alkyl (such as methyl or ethyl), CF₃,C₁₋₄ alkoxy (such as methoxy), S(O)₂(C₁₋₄ alkyl) (for example S(O)₂CH₃),S(O)NH₂, S(O)₂NH(C₁₋₄ allyl), S(O)₂N(C₁₋₄ alkyl)₂ or OCF₃.

In a further aspect the present invention provides a compound of formula(I) or (Ia) wherein R⁹ is isoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl,quinolinyl or 2-oxo-1,2-dihydroquinolinyl; each optionally substitutedby halogen (such as fluorine), C₁₋₄ alkyl (such as methyl or ethyl),CF₃, C₁₋₄ alkoxy (such as methoxy), S(O)₂(C₁₋₄ alkyl) (for exampleS(O)₂CH₃) or OCF₃.

In a still further aspect R⁹ is 1-oxo-1,2-dihydroisoquinolinyloptionally substituted by halogen (such as fluorine), C₁₋₄ alkyl (suchas methyl or ethyl), CF₃, C₁₋₄ alkoxy (such as methoxy), S(O)₂(C₁₋₄alkyl) (for example S(O)₂CH₃) or OCF₃. Alternatively, R⁹ is2-oxo-1,2-dihydroquinolinyl optionally substituted by halogen (such asfluorine), C₁₋₄ allyl (such as methyl or ethyl), CF₃, C₁₋₄ alkoxy (suchas methoxy), S(O)₂(C₁₋₄ alkyl) (for example S(O)₂CH₃) or OCF₃.

In another aspect R⁹ is an oxo-substituted dihydropyridinyl (such as6-oxo-1,6-dihydropyridin-3-yl, 2-oxo-1,2-dihydropyridin-5-yl or2-oxo-1,2-dihydropyridin-4-yl), an oxo-substituted dihydroisoquinolinyl(such as 1-oxo-1,2-dihydroisoquinolinyl), an oxo-substituteddihydrophthalazinyl (such as 4-oxo-3,4-dihydrophthalazin-1-yl),pyrazinyl (such as pyrazinyl), pyrrolyl (such as pyrrol-3-yl) or indolyl(such as indol-3-yl), each of which is not further substituted orsubstituted by halogen (such as chloro or fluoro), C₁₋₄ alkyl (such asmethyl), CF₃ or C₃₋₅ cycloalkyl (such as cyclopropyl).

In a further aspect R⁹ is an oxo-substituted dihydropyridinyl (such as6-oxo-1,6-dihydropyridin-3-yl, 2-oxo-1,2-dihydropyridin-5-yl or2-oxo-1,2-dihydropyridin-4-yl), an oxo-substituted dihydroisoquinolinyl(such as 1-oxo-1,2-dihydroisoquinolinyl-4-yl) or pyrazinyl (such aspyrazinyl-4-yl), each of which is not further substituted or substitutedby: halogen (such as chloro or fluoro), C₁₋₄ alkyl (such as methyl) orCF₃.

An example of a compound of formula (I) or (Ia) is:

-   N-{(2R)-3-[4(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(methylsulfonyl)benzamide;-   N-{(2R)-3-[4(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4-(methylsulfonyl)benzamide;-   2-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4-(methylsulfonyl)benzamide;-   4-amino-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-methoxybenzamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-(methylsulfonyl)benzamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-(methylsulfonyl)thiophene-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}quinoline-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxamide    acetate salt-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-fluoroimidazo[1,2-a]pyridine-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1,3-benzothiazole-6-carboxamide;-   3-cyano-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide;-   N-{4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-3-hydroxybutyl}-2-(methylsulfonyl)benzamide;-   N-{4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-3-hydroxybutyl}-2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxamide;-   4-amino-N-{4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-3-hydroxybutyl}-3-methoxybenzamide;-   N-{4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxybutyl}-2-(methylsulfonyl)benzamide;-   N-{(2R)-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(methylsulfonyl)benzamide;-   N-{(2R)-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2-S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(methylsulfonyl)benzamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-[(methylamino)sulfonyl]benzamide;-   3,5-bis(acetylamino)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide;-   3-(Acetylamino)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1H-pyrazole-4-carboxamide;-   2-(Acetylamino)-5-bromo-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-oxo-1,2-dihydropyridine-3-carboxamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-5-carboxamide;-   N-{(2R)-3-[4(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}quinoline-4-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1H-indole-4-carboxamide;-   2-(Acetylamino)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide;-   2-Acetylamino)-5-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide;-   2-(Acetylamino)-4-chloro-N-{(2R)-3-[4(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide;-   5-Chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-[(methylsulphonyl)amino]benzamide;-   4-Chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-[(methylsulphonyl)amino]benzamide;-   2-Amino-4-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide;-   5-Chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-oxo-1,6-dihydropyridine-3-carboxamide;-   2-(Aminosulphonyl)-4-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1H-indazole-3-carboxamide;-   1-tert-Butyl-N-{(2R)-3-[4(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-methyl-1H-pyrazole-5-carboxamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}4,5,6,7-tetrahydro-2H-indazole-3-carboxamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-(tifuoromethyl)-1H-pyrazole-4-carboxamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-methylimidazo[1,2-a]pyridine-3-carboxamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4(1H-pyrazol-3-yl)benzamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}cinnoline-4-carboxamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-hydroxyquinoline-4-carboxamide;-   N-{3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4-oxo-3,4-dihydrophthalazine-1-carboxamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1H-indole-3-carboxamide;-   N-{(2R)-3-[4-(4-Chlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(methylsulfonyl)benzamide;-   N-{(2R)-3-[(4-Chlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2R)-3-[4    Chloro-3-fluorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2R)-3-[4-(3,4-Difluorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-N-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-N-methyl-1H-indazole-3-carboxamide;-   N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-N-methyl-4-oxo-3,4-dihydrophthalazine-1-carboxamide;-   Benzoic acid,    3-[[2-[[(2R)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl]amino]-2-oxoethyl]amino]-,    methyl ester;-   Propanamide,    N-[2-[[2-[[(2R)-3-[4(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl]amino]-2-oxoethyl]amino]phenyl]-;-   Propanamide,    N-[2-[[2-[[(2R)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl]amino]-2-oxoethyl]amino]phenyl]-;-   (2-S)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-hyroxy-2-phenylethanamide;-   2-[2-({(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}amino)-2-oxoethoxy]benzamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]acetamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-methoxybenzamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(methylamino)benzamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}nicotinamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}isonicotinamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-(dimethylamino)benzamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(1,3-oxo-1,3-dihydro-2H-isoindol-2-yl)acetamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-hydroxynicotinamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(1H-indol-3-yl)acetamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide;-   N-{(2R)-3-[4-(3-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}4,7-dimethylpyrazolo[5,1-c][1,2,4]triazine-3-carboxamide;-   N-{(2R)-3-[4-(3-4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}pyrazine-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-9H-purine-6-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}quinoline-6-carboxamide;-   N-{(2R)-3-[4-(3-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2,7-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(pyrimidin-2-ylthio)acetamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-fluoro-1H-indole-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1,3-benzothiazole-6-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-phenyl-1,3-oxazole-4-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-hydroxypyridine-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-hydroxypyridine-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl})-1H-benzimidazole-5-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1H-indole-5-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-methyl-1H-indole-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1H-imidazole-4-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1H-indole-6-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-methyl-1H-indole-3-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1H-indole-7-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-[(methylamino)sulfonyl]benzamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3,4-bis(methylsulfonyl)benzamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-pyridin-3-ylacetamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-hydroxy-1H-indole-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1,5-dimethyl-1H-pyrazole-3-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-methylsulfonyl)    1H-indole-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}quinoxaline-6-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1,8-naphthyridine-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}imidazo[2,1-b][1,3]benzothiazole-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide;-   N-{(2R-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-oxo-2,3-dihydro    1H-indazole-4-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-hydroxy-1H-indazole-6-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide;-   2-(1H-benzimidazol-1-yl)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}acetamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-ethyl-3-methyl-1H-pyrazole-5    carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-methyl-1H-pyrazole-3-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide;-   6-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}imidazo[1,2-a]pyridine-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-methylimidazo[1,2-a]pyridine-3-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}imidazo[1,2-a]pyrimidine-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-[(4-methylpyrimidin-2-yl)thio]acetamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4-hydroxyquinoline-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}quinoline-8-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-methylimidazo[1,2-a]pyridine-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}imidazo[1,2-a]pyridine-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1,6-naphthyridine-2-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2,1,3-benzoxadiazole-5-carboxamide    1-oxide;-   N-{(2R))-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-oxo-1,6-dihydropyridine-3-carboxamide;-   4-Chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1H-pyrazole-3-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-phenyl-1,3-oxazole-4-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3,5-dimethyl-1H-pyrazole-4-carboxamide;-   (2-R)-2-Acetylamino)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-phenylethanamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(2-hydroxyphenyl)acetamide;-   (2R)-N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-2-phenylethanamide;-   (2S)-2-(Acetylamino)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-phenylethanamide;-   (2S)-N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-2-phenylethanamide;-   1-{(R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-o-tolyl-urea;-   1-{(R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-p-tolyl-urea;-   N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxy-2-methylpropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxy-2-methylpropyl}-2-oxo-1,2-dihydroquinoline-4-carboxamide;-   N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxy-2-methylpropyl}oxo-3,4-dihydrophthalazine-1-carboxamide;-   (2S)N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxy-2-methylpropyl}-2-hydroxy-2-phenethanamide;-   N-{(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl)-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-((2R)-3-{4-[2-Aminocarbonyl)-(3,4-dichlorophenoxy]piperidin-1-yl-2-hydroxypropyl}1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   3-Cyano-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzenesulfonamide;-   5-[({(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}amino)-sulfonyl]-2-methoxybenzamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-sulfonamide    acetate salt;-   N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-(2,4-difluorobenzenesulfonamide;-   N-{(2S)-3-[(4,3-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}methanesulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzenesulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-phenylmethanesulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4-methoxybenzenesulfonamide;-   N-({5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}amino)sulfonyl]-2-thienyl}methyl)benzamide;-   4-cyano-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzenesulfonamide;-   N-{5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}amino)sulfonyl]-4-methyl-1,3-thiazol-2-yl}acetamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}thiophene-2-sulfonamide;-   4-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}amino)sulfonyl]benzoic    acid;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2,5-dimethoxybenzenesulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}4    (phenylsulfonyl)thiophene-2-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-(1,3-oxazol-5-yl)thiophene-2-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylthiophene-2-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-pyridin-2-ylthiophene-2-sulfonamide;-   5-chloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1,3-dimethyl-1H-pyrazole-4-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3,5-dimethylisoxazole-4-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2,1,3-benzothiadiazole-4-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-methyl-1H-imidazole-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2,1,3-benzoxadiazole-4-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-isoxazol-3-ylthiophene-2-sulfonamide;-   methyl    3-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}amino)sulfonyl]thiophene-2-carboxylate;-   2,6-dichloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzenesulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-methylbenzenesulfonamide;-   3-chloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzenesulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}propane-2-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}propane-1-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-methyl-1-phenyl-1H-pyrazole-4-sulfonamide;-   3-chloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-methylbenzenesulfonamide;-   methyl    5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}amino)sulfonyl]-2-methyl-3-furoate;-   methyl    5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}amino)sulfonyl]-1-methyl-1H-pyrrole-2-carboxylate;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3,4-dimethoxybenzenesulfonamide;-   5-chloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}thiophene-2-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-morpholin-4-ylpyridine-3-sulfonamide;-   N-2-chloro-4-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}amino)sulfonyl]phenyl}acetamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2,3-dihydroxyquinoxaline-6-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2,4-dimethoxybenzenesulfonamide;-   5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}amino)sulfonyl]-2-methoxybenzamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-methylbenzenesulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2,4-dimethyl-1,3-thiazole-5-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-hydroxyquinoxaline-6-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}pyridine-3-sulfonamide;-   4′-cyano-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}biphenyl-2-sulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1,2-dimethyl-1H-imidazole-4-sulfonamide;-   4-acetyl-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzenesulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4-(methylsulfonyl)benzenesulfonamide;-   2-chloro-4-cyano-N-{(2S)-3-[(3,4-dichlorophenoxy)-piperidin-1-yl]-2-hydroxypropyl}benzenesulfonamide;-   N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1,3,5-trimethyl-1H-pyrazole-4-sulfonamide;-   N-[(2R)-3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxamide;-   N-{(2S)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide    acetate;-   N-{(2S)-3-{4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2S)-3-{4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-[(methylamino)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-{[(2-hydroxyethyl)amino]sulfonyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide    acetate salt;-   7-[(Cyclopropylamino)sulfonyl]-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   7-(Azetidin-1-ylsulfonyl)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide    acetate salt;-   7-(Aminosulfonyl)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-[(dimethylamino)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-[(3-hydroxy-3-methylazetidin-1-yl)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxamide    acetate;-   N-[(2R)-3-(4-{3,4-Dichloro-2-[(cyclopropylamino)carbonyl]phenoxy}piperidin-1-yl)-2-hydroxypropyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxamide    acetate salt;-   N-{(2R)-3-[4-(3-Chlorocyanophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-((2R)-2-Hydroxy-3-{4-[4-(methylsulfonyl)phenoxy]piperidin-1-yl}propyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-((2R)-3-[4-(4-Cyanophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-((2R)-3-{4-[2-(Aminocarbonyl)-4-chlorophenoxy]piperidin-1-yl}-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-[(2R)-3-(4-{4-Chloro-2-[(methylamino)carbonyl]phenoxy}piperidin-1-yl)-2-hydroxypropyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   Methyl    5-chloro-2-{[1-((2R)-2-hydroxy-3-{[(1-oxo-1,2-dihydroisoquinolin-4-yl)carbonyl]amino}propyl)piperidin-4-yl]oxy}benzoate    acetate salt;-   N-((2R)-3-{4-[2-(Aminosulfonyl)-3,4-dichlorophenoxy]piperidin-1-yl}-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide    trifluoroacetate salt;-   N-[(2R)-3-(4-{3,4-Dichloro-2-[(methylamino)sulfonyl]phenoxy}piperidin-1-yl)-2-hydroxypropyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxamide    acetate salt;-   N-[(2R)-3-(4-{3,4-Dichloro-2-[(cyclopropylamino)sulfonyl]phenoxy}piperidin-1-yl)-2-hydroxypropyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxamide    acetate salt-   N-{(2R)-3-[4-(3-Chloro-4-cyanophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2R)-3-{4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxy-2-methylpropyl}-6-(methylsulphonyl)-1H-indole-3-carboxamide;-   N-{(2R)-3-{4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-(methylsulphonyl)-1H-indole-3-carboxamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide    acetate salt;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide    acetate salt;-   N-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide    acetate salt;-   N-(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]2-hydroxypropyl}-6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-{(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;-   N-((2R)-3-{4-[3,4-Dichloro-2-(methylsulfonyl)phenoxy]piperidin-1-yl}-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide    acetate salt,-   N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide    acetate salt;-   N-{(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide    acetate salt;-   N-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;-   {(2-R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(2-oxoquinoxalin-1-(2H)-yl)acetamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide;-   N-{(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide;-   N-{(2R)-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide;-   N-{(2R)-3-{4-(3,4-dichlorophenoxy)piperidin-1-yl}-2-hydroxypropyl}-1-oxo-1,2-dihydro-2-methylisoquinoline-4-carboxamide;-   N-{(2R)-3-{4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-oxo-1,2-dihydro-1-methylquinoline-4-carboxamide;-   N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide;    or,-   N-{(2R)-3-[4-(4-chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide.

A compound of formula (I) or (Ia) can be prepared by reacting a compoundof formula (II):

wherein X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R³², m and n are as definedabove, with:

-   -   (i) when Y is a bond, CH₂, NR³⁵, CH₂NH, CH₂NHC(O), CH(OH),        CH(NHCOR³³), CH(NHSO₂R³⁴), CH₂O or CH₂S, Z is C(O), R³⁵ is not        hydrogen and, R³³ and R³⁴ are as defined above, a compound of        formula (IIIa):        L¹-CO—Y—R⁹  (IIIa)        wherein R⁹ is as defined above and L¹ is a leaving group (for        example a hydroxyl or chloride leaving group) in the presence of        a base (for example diisopropylelthylamine), optionally in the        presence of a coupling agent (for example        bromo-tris-pyrrolidinophosphonium hexafluorophosphate, PyBrOP or        O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate); and,    -   (ii) when Y is NH and Z is C(O), a compound of formula (IIIb):

wherein R⁹ is as defined above.

-   -   (iii) when Y is a bond and Z is S(O)₂, a compound of formula        (IIIc):        L¹-S(O)₂—R⁹  (IIIc)        wherein R⁹ is as defined above and L¹ is a leaving group (for        example a hydroxyl or chloride leaving group) in the presence of        a base (for example pyridine).

A compound of formula (II) can be prepared as described in WO 00/58305or WO 01/77101, or by reacting a compound of formula (IV):

wherein X and R¹ are as defined above, with:

-   -   (i) when m and n are 0, R², R³, R⁵ and R⁶ are hydrogen, and R⁴        and R³² are as defined for formula (I), a compound of formula        (V):

in which L² is a leaving group (for example chloro ornosyloxy{3-NO₂—C₆H₄—S(O)₂O—}) followed by reaction with ammonia, anamine R³²—NH₂ or with sodium azide and subsequent reduction with, forexample, triphenylphosphine;

-   -   (ii) when m and n are 0, R² and R³ are hydrogen and R³² are as        defined for formula (I), with a compound of formula (VI):

in which P¹ and P² are, alone or together, suitable protective groups(for example together they form phthalamide), or either P¹ or P² is R³²,followed by deprotection using, for example when P¹ and P² formphthalamide, hydrazine;

-   -   (iii) when m is 0, n is 1, R² and R³ are hydrogen and R⁴, R⁵,        R⁶, R⁷, R⁸ and R³² are as defined for formula (I), with a        compound of formula (VII):

in which P¹ and P² are, alone or together, suitable protective groups(for example together they form phthalamide), or either P¹ or P² is R³²,followed by deprotection using, for example when P¹ and P² formphtalamide, hydrazine;

-   -   (iv) when m and n are 1, R² and R³ are hydrogen and R⁴, R⁵, R⁶,        R⁷, R⁸ and R³² are as defined for formula (I), with a compound        of formula (VIII):

in which L² is as defined for formula (V) and P¹ and P² are, alone ortogether, suitable protective groups (for example together they formphthalamide), or either P¹ or P² is R³², followed by deprotection using,for example when P¹ and P² form phthalamide, hydrazine;

-   -   (v) when m is 1 and n is 0, R² and R³ are hydrogen, R⁵ and R⁶        are, independently, hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl, and        R⁴ and R³² are as defined for formula (I), with a compound of        formula (IX):

in which L² is as defined for formula (V) and P¹ and P² are, alone ortogether, suitable protective groups (for example together they formphthalamide), or either P¹ or P² is R³², followed by deprotection using,for example when P¹ and P² form phthalamide, hydrazine;

-   -   (vi) when m is 1 and n is 0, R², R³, R⁵ and R⁶ are hydrogen and        R⁴ and R³² are as defined for formula (I), with a compound of        formula (X):

in which L² is a leaving group (for example bromine) followed byreaction with ammonia, an amine R³²—NH₂ or with sodium azide andsubsequent reduction with, for example, triphenylphosphine;

-   -   (vii) when m is 1 and n is 0, R², R³, R⁵ and R⁶ are,        independently, hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl, and R¹,        R⁴ and R³² are as defined for formula (I), with a compound of        formula (XI):

in which P¹ and P² are, alone or together, suitable protective groups(for example together they form phthalamide), or either P¹ or P² is R³²,followed by hydride reduction (for example with sodium borohydride), orby adding an appropriate organometallic species (for example R⁴MgX,where X is a halide); or,

-   -   (viii) when m is 1 and n is 1, R², R³, R⁵, R⁶, R⁷ and R⁸ are,        independently, hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl, and R¹,        R⁴ and R³² are as defined for formula (I), with a compound of        formula (XII):

in which P¹ and P² are, alone or together, suitable protective groups(for example together they form phthalamide), or either P¹ or P² is R³²,followed by hydride reduction (for example with sodium borohydride), orby adding an appropriate organometallic species (for example R⁴MgW,where W is a halide).

When m is 0 and n is 0, R², R³, R⁵ and R⁶ are, independently, hydrogen,C₁₋₆ alkyl or C₃₋₆ cycloalkyl, compounds or formula (II) can be preparedby reacting a compound of formula (XIII):

wherein X and R¹ are as defined for formula (I), and L³ is hydrogen or aleaving group (for 4 example ethoxy, N,O-dimethylhydroxylamine), with acompound of formula (XIV):M-CR⁵R⁶—CO-L⁴  (XIV)in which M represents a metal (for example Li or Na) and L⁴ is an aminogroup (for example ammonium) followed by rearrangement (for example withphenyliodonium diacetate, Tetrahedron Letters, 2001, 42, 1449.) andappropriate reduction (for example with sodium borohydride), or anappropriate organometalic addition (for example R⁴MgW, where W is ahalide).

When m is 0, n is 1 and R², R³, R⁵, R⁶, R⁷ and R⁸ are, independently,hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl, compounds of formula (II) canbe prepared by reacting a compound of formula (XX):

wherein X, R¹ and R⁴ are as described in formula (I) above and Z is analdehyde protective group (for example cyanohydrin or dithiane), with acompound of formula (XXI):CR⁵R⁶═CR⁷R⁸—C(O)-L⁵  (XXI)in which R⁵, R⁶, R⁷ and R⁸ are as described above, and L⁵ is an alkoxyor amino group (for example ethoxy or ammonium) in presence of a base(for example LDA or n-butylithium), followed by hydrolytic removal ofthe group L⁵, rearrangement (for example with phenyliodonium diacetate)and appropriate reduction (for example with sodium borohydride), or anappropriate organometalic addition (for example R⁴MgW, where W is ahalide).

A compound of formula (V) can be prepared by reacting a compound offormula (XXII):

with a peracid (for example meta-chloroperbenzoic acid) or usingSharpless asymmetric epoxidation conditions (J. Am. Chem. Soc. 1980,102, 5974-5976), followed by activation of the alcohol as a leavinggroup (for example as nosyloxy).

A compound of formula (VI) can be prepared:

-   -   (a) when both R⁵ and R⁶ are hydrogen, by reacting a compound of        formula (XXIII):

with a peracid (for example meta-chloroperbenzoic acid) or usingSharpless asymmetric epoxidation conditions, followed, for example, by aMitsunobu reaction using phthalimide, 1,1-(azodicarbonyl)dipiperidineand tibutylphosphine (Tetrahedron Lett. 1993, 34, 1639).

(b) when R⁵ and R⁶ are, independently, hydrogen, C₁₋₆ alkyl or C₃₋₆cycloalkyl, by reacting a compound of formula (XXIV):

in which P¹ and P² are, alone or together, suitable protective groups(for example together they form phthalamide), or either P¹ or P² is R³²,with a sulphur ylide (for example trimethylsulfoniummethylide, J. Am.Chem. Soc. 1965, 87, 1353-1364); or a phosphonium ylide (for exampletiphenylphosphoniummethylide); followed by epoxidation of the resultingalkene using a peracid (for example meta-chloroperbenzoic acid).

A compound of formula (VII) can be prepared by reacting a compound offormula (XXV):

in which P¹ and P² are, alone or together, suitable protective groups(for example together they form phthalamide), or either P¹ or P² is R³²,with a sulfur ylide (for example trimethylsulfoniummethylide), or aphosphonium ylide (for example tiphenylphosphoniummethylide) followed byepoxidation of the resulting alkene using a peracid (for examplemeta-chloroperbenzoic acid).

A compound of formula (VIM can be prepared by reacting a compound offormula (XXV) with the anion of ethyl acetate (which can be prepared bythe action of lithium diisopropylamide on ethyl acetate) followed byreduction of the resulting ester, or with, for example, vinyl magnesiumGrignard and subsequent hydroboration (for example cathecholborane)/oxidation (for example hydrogen peroxide) of the alkene.

A compound of formula (IX) can be prepared from a compound of formula(XXIV) in a similar way as for compound (VIII).

A compound of formula (X) can be prepared by reacting a compound offormula (XXVI):

with a peracid (for example meta-chloroperbenzoic acid), followed byselective activation of the primary alcohol as a leaving group (forexample nosyloxy).

Further, compounds of formula (I) and (Ia) can be prepared by or byroutine adaptation of: the routes described above, methods described inthe art, or the Examples recited below. The intermediates identifiedabove are commercially available or can be prepared by using or adaptingmethods described in the art.

In a further aspect of the invention there is provided a process forpreparing 4-(3,4-dichlorophenoxy)piperidine comprising the steps of:

-   -   a. reacting 4-hydroxypiperidine with a suitable base in a        suitable solvent at room temperature; and,    -   b. heating the mixture so produced together with        1,2-dichloro-4-fluorobenzene at a temperature in the range        50-90° C., or at reflux of the solvent used.

In a further aspect the present invention provides a process forpreparing 4-(3,4-dichlorophenoxy)piperidine comprising reacting4-hydroxypiperidine with a suitable base {such as an alkali metal(preferably sodium or potassium) C₁₋₁₀ alkoxide [such as a C₄₋₁₀tertiary alkoxide (for example a C₄₋₆ tertiary alkoxide)], for examplepotassium tert-butoxide or potassium 3,7-dimethyl-3-octanoxide} in asuitable solvent {such as: an ether [for example tetrahydrofuran ormethyl tert-butyl ester], an aromatic solvent [such as toluene] or amixture of these solvents} at room temperature (10-30° C.); heating themixture so produced together with 1,2-dichloro-4-fluorobenzene at atemperature in the range 50-90° C., or at reflux of the solvent used.

In a still further aspect the present invention provides a process forpreparing 4 (3,4-dichlorophenoxy)piperidine comprising reacting4-hydroxypiperidine with a suitable base {such as an alkali metal(preferably sodium or potassium) C₁₋₁₀ alkoxide (such as a C₄₋₁₀tertiary alkoxide), for example a C₁₋₆ alkoxide (such as a C₄₋₆ tertiaryalkoxide), for example potassium tert-butoxide} in a suitable solvent{such as: an ether [for example tetrahydrofuran or methyl tert-butylester], an aromatic solvent [such as toluene] or a mixture of thesesolvents} at room temperature (10-30° C.), and heating the mixture soproduced to a temperature in the range 50-90° C., or at reflux of thesolvent used, and adding 1,2-dichloro-4-fluorobenzene.

Examples of tertiary alkoxides are potassium tert-butoxide and potassium3,7-dimethyl-3-octanoxide.

In another aspect the present invention provides processes for thepreparation of compounds of formula (I) and (Ia).

The intermediates of formula (VI), (VII) and (VIII) defined herein arenovel and these intermediates, and processes for their preparation, areprovided as further features of the invention.

The compounds of the invention have activity as pharmaceuticals, inparticular as modulators of chemokine receptor (especially CCR3)activity, and may be used in the treatment of autoimmune, inflammatory,proliferative or hyperproliferative diseases, orimmunologically-mediated diseases (including rejection of transplantedorgans or tissues and Acquired Immunodeficiency Syndrome (AIDS)).

In one aspect examples of these conditions are:

-   (1) (the respiratory tract) obstructive diseases of airways    including: chronic obstructive pulmonary disease (COPD) (such as    irreversible COPD); asthma {such as bronchial, allergic, intrinsic,    extrinsic or dust asthma, particularly chronic or inveterate asthma    (for example late asthma or airways hyper-responsiveness)};    bronchitis {such as eosinophilic bronchitis}; acute, allergic,    atrophic rhinitis or chronic rhinitis including rhinitis caseosa,    hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or    rhinitis medicamentosa; membranous rhinitis including croupous,    fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis;    seasonal rhinitis including rhinitis nervosa (hay fever) or    vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases;    nasal polyposis; fibroid lung, idiopathic interstitial pneumonia,    antitussive activity, treatment of chronic cough associated with    inflammatory conditions of the airways or iatrogenic induced cough;-   (2) (bone and joints) arthrides including rheumatic, infectious,    autoimmune, seronegative spondyloarthropathies (such as ankylosing    spondylitis, psoriatic arthritis or Reiter's disease), Behcet's    disease, Sjogren's syndrome, or systemic sclerosis;-   (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis    or other eczmatous dermitides, seborrhoetic dermatitis, Lichen    planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa,    urticaria, angiodermas, vasculitides erythemas, cutaneous    eosinophilias, uveitis, Alopecia greata or vernal conjunctivitis;-   (4) (gastrointestinal tract) Coeliac disease, proctitis,    eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,    ulcerative colitis, irritable bowel disease or food-related    allergies which have effects remote from the gut (for example    migraine, rhinitis or eczema);-   (5) (Allograft rejection) acute and chronic following, for example,    transplantation of kidney, heart, liver, lung, bone marrow, skin or    cornea; or chronic graft versus host disease; and/or-   (6) (other tissues or diseases) Alzheimer's disease, multiple    sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome    (AIDS), Lupus disorders (such as lupus erythematosus or systemic    lupus), erythematosus, Hasbimoto's thyroiditis, myasthenia gravis,    type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper    IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal    disease, Sezary syndrome, idiopathic thrombocytopenia pupura or    disorders of the menstrual cycle.

The compounds of the invention are also H1 antagonists and may be usedin the treatment of allergic disorders.

The compounds of the invention may also be used to control a sign and/orsymptom of what is commonly referred to as a cold (for example a signand/or symptom of a common cold or influenza or other associatedrespiratory virus infection).

According to a further feature of the invention there is provided acompound of formula (I) or (Ia), or a pharmaceutically acceptable saltthereof or a solvate thereof, for use in a method of treatment of a warmblooded animal (such as man) by therapy (including prophylaxis).

According to a further feature of the present invention there isprovided a method for modulating chemokine receptor activity (especiallyCCR3 receptor activity), or antagonising H1, in a warm blooded animal,such as man, in need of such treatment, which comprises administering tosaid animal an effective amount of a compound of the formula (I) or(Ia), or a pharmaceutically acceptable salt thereof or a solvatethereof.

The invention also provides a compound of the formula (I) or (Ia), or apharmaceutically acceptable salt thereof or a solvate thereof, for useas a medicament.

In another aspect the invention provides the use of a compound offormula (I) or (Ia), or a pharmaceutically acceptable salt thereof or asolvate thereof, in the manufacture of a medicament for use in therapy(for example modulating chemokine receptor activity (especially CCR3receptor activity), or antagonising H1, in a warm blooded animal, suchas man).

The invention further provides the use of a compound of formula (I) or(Ia), or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for use in the treatment of

-   (1) (the respiratory tract) obstructive diseases of airways    including: chronic obstructive pulmonary disease (COPD) (such as    irreversible COPD); asthma {such as bronchial, allergic, intrinsic,    extrinsic or dust asthma, particularly chronic or inveterate asthma    (for example late asthma or airways hyper-responsiveness)};    bronchitis {such as eosinophilic bronchitis}; acute, allergic,    atrophic rhinitis or chronic rhinitis including rhinitis caseosa,    hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or    rhinitis medicamentosa; membranous rhinitis including croupous,    fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis;    seasonal rhinitis including rhinitis nervosa (hay fever) or    vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases;    nasal polyposis; fibroid lung, idiopathic interstitial pneumonia,    antitussive activity, treatment of chronic cough associated with    inflammatory conditions of the airways or iatrogenic induced cough;-   (2) (bone and joints) arthrides including rheumatic, infectious,    autoimmune, seronegative spondyloarthropathies (such as ankylosing    spondylitis, psoriatic arthritis or Reiter's disease), Behcet's    disease, Sjogren's syndrome or systemic sclerosis;-   (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis    or other eczmatous dermitides, seborrhoetic dermatitis, Lichen    planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa,    urticaria, angiodermas, vasculitides erythemas, cutaneous    eosinophilias, uveitis, Alopecia greata or vernal conjunctivitis;-   (4) (gastrointestinal tract) Coeliac disease, proctitis,    eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,    ulcerative colitis, irritable bowel disease or food-related    allergies which have effects remote from the gut (for example    migraine, rhinitis or eczema);-   (5) (Allograft rejection) acute and chronic following, for example,    transplantation of kidney, heart, liver, lung, bone marrow, skin or    cornea; or chronic graft versus host disease; and/or-   (6) (other tissues or diseases) Alzheimer's disease, multiple    sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome    (AIDS), Lupus disorders (such as lupus erythematosus or systemic    lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis,    type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper    IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal    disease, sezary syndrome, idiopathic thrombocytopenia pupura or    disorders of the menstrual cycle; in a warm blooded animal, such as    man.

In a further aspect a compound of formula (I) or (Ia), or apharmaceutically acceptable salt thereof, is useful in the treatment ofasthma {such as bronchial, allergic, intrinsic, extrinsic or dustasthma, particularly chronic or inveterate asthma (for example lateasthma or airways hyper-responsiveness)}; or rhinitis {including acute,allergic, atrophic or chronic rhinitis, such as rhinitis caseosa,hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitismedicamentosa; membranous rhinitis including croupous, fibrinous orpseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitisincluding rhinitis nervosa (hay fever) or vasomotor rhinitis}.

In a still further aspect a compound of formula (I) or (Ia), or apharmaceutically acceptable salt thereof, is useful in the treatment ofasthma.

The present invention also provides the use of a compound of formula (I)or Ia), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of asthma orrhinitis.

The present invention further provides a method of treating a chemokinemediated disease state (especially a CCR3 mediated disease state,especially asthma) in a warm blooded animal, such as man, whichcomprises administering to a mammal in need of such treatment aneffective amount of a compound of formula (I) or (Ia), or apharmaceutically acceptable salt thereof or solvate thereof.

In order to use a compound of the invention, or a pharmaceuticallyacceptable salt thereof or solvate thereof, for the therapeutictreatment of a warm blooded animal, such as man, in particularmodulating chemokine receptor (for example CCR3 receptor) activity orantagonising H1, said ingredient is normally formulated in accordancewith standard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula (I)or (Ia), or a pharmaceutically acceptable salt thereof or a solvatethereof (active ingredient), and a pharmaceutically acceptable adjuvant,diluent or carrier. In a further aspect the present invention provides aprocess for the preparation of said composition which comprises mixingactive ingredient with a pharmaceutically acceptable adjuvant, diluentor carrier. Depending on the mode of administration, the pharmaceuticalcomposition will preferably comprise from 0.05 to 99% w (percent byweight), more preferably from 0.05 to 80% w, still more preferably from0.10 to 70% w, and even more preferably from 0.10 to 50% w, of activeingredient, all percentages by weight being based on total composition.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease condition that it is desired to treat,for example by topical (such as to the Jung and/or airways or to theskin), oral, rectal or parenteral administration. For these purposes thecompounds of this invention may be formulated by means known in the artinto the form of, for example, aerosols, dry powder formulations,tablets, capsules, syrups, powders, granules, aqueous or oily solutionsor suspensions, (lipid) emulsions, dispersible powders, suppositories,ointments, creams, drops and sterile injectable aqueous or oilysolutions or suspensions.

A suitable pharmaceutical composition of this invention is one suitablefor oral administration in unit dosage form, for example a tablet orcapsule which contains between 0.1 mg and 1 g of active ingredient.

In another aspect a pharmaceutical composition of the invention is onesuitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, an intravenous, subcutaneous orintramuscular dose of 0.01 mgkg⁻¹ to 100 mgkg⁻¹ of the compound,preferably in the range of 0.1 mgkg⁻¹ to 20 mgkg⁻¹ of this invention,the composition being administered 1 to 4 times per day. Theintravenous, subcutaneous and intramuscular dose may be given by meansof a bolus injection. Alternatively the intravenous dose may be given bycontinuous infusion over a period of time. Alternatively each patientwill receive a daily oral dose which is approximately equivalent to thedaily parenteral dose, the composition being administered 1 to 4 timesper day.

The invention will now be illustrated by the following non-limitingExamples in which, unless stated otherwise:

(i) when given, ¹H NMR data is quoted and is in the form of delta valuesfor major diagnostic protons, given in parts per million (ppm) relativeto tetramethylsilane CMS) as an internal standard, determined at 300 MHzor 400 MHz using perdeuterio DMSO-D6 (CD₃SOCD₃), methanol-D4 (CD₃OD) orCDCl₃ as the solvent unless otherwise stated;(ii) mass spectra (MS) were run with an electron energy of 70 electronvolts in the chemical ionisation (CI) mode using a direct exposureprobe; where indicated ionisation was effected by electron impact (EI)or fast atom bombardment (FAB) or electrospray (ESI); where values form/z are given, generally only ions which indicate the parent mass arereported, and unless otherwise stated the mass ion quoted is thepositive mass ion—(M+H)⁺;(iii) the title and sub-title compounds of the examples and methods werenamed using the ACD/Index name program version 4.55 from AdvancedChemistry Development, Inc;(iv) unless stated otherwise, reverse phase HPLC was conducted using aSymmetry, NovaPak or Xterra reverse phase silica column; and(v) the following abbreviations are used:

APCI Atmospheric pressure CI DMF N,N-dimethylformamide HPLC Highpressure liquid chromatography MTBE Methyl tert-butyl ether DMSOdimethylsulfoxide THF tetrahydrofuran DCM dichloromethane

Preparation 1(2R)-1-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol Step1:2-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1H-isoindole-1,3-(2H)-dione

(R)-2-Oxiranylmethyl)-1H-isoindole-1,3-(2H)-dione (TetrahedronAsymmetry, 1996, 7, 1641, 5 g) in a mixture of 50 ml of ethanol and 15ml of DMF was treated with 4 (3,4-dichlorophenoxy)-piperidine (6 g). Themixture was stirred overnight at room temperature. The solution wasconcentrated under vacuum and the residue was azeotroped twice withtoluene. The crude material was purified by chromatography (ethylacetate) to give the subtitle compound as a yellow oil.

MS (APCI) 449/451 (M+H)⁺

¹H NMR δ (CDCl₃) 7.92-7.81 (2H, m), 7.77-7.70 (2H, m), 7.30 (1H, d);6.98 (1H, t), 6.74 (1H, dt), 4.34-4.20 (1H, m), 4.09-3.97 (1H, m), 3.83(1H, dd), 3.73 (1H, dd), 2.93-2.79 (1H, m), 2.73-2.60 (1H, m), 2.59-2.37(3H, m), 2.31 (1H, t), 2.02-1.86 (2H, m), 1.86-1.67 (2H, m).

Step 2:(2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol

(S)-2-[3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl]-1H-isoindole-1,3(2H)-dione(4 g) in ethanol (100 ml) was treated with 20 ml of hydrazinemonohydrate and the resulting mixture was refluxed for 3 h. The reactionwas cooled and filtered. The filtrate was evaporated and the product waschromatographed (ethyl acetate) to give the title compound as a yellowoil which solidified on standing (2.5 g).

MS (APCI) 319/321 (M+H)⁺

¹H NMR δ (CDCl₃) 7.31 (1H, d), 7.00 (1H, d), 6.75 (1H, dd), 4.00 (1H,app. sept), 3.74-3.62 (1H, m), 2.94-2.84 (1H, m), 2.82 (1H, d),2.72-2.61 (1H, m), 2.65 (1H, d); 2.60-2.49 (1H, m), 2.46-2.21 (3H, m),2.06-1.91 (2H, m), 1.90-1.72 (2H, m).

Preparation 24-Amino-1-[4-(3,4-dichlorophenoxy)piperidin-1-yl]butan-2-ol Step 1:2-{4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-3-hydroxybutyl}-1H-isoindole-1,3(2H)-dione

A mixture of 4-(3,4-dichlorophenoxy)piperidine (WO 0058305, WO 0177101)(4.40 g) and 2-(2-oxiran-2-ylethyl)-1H-isoindole-1,3(2H)-dione (J. Med.Chem. 1979, 22(6), 631-9. 5.00 g) in ethanol (50 ml) was stirred at 60°C. for 12 h. The mixture was cooled down and left overnight. The formedcrystals were collected by filtration, washed with cold ethanol anddried under vacuum to afford the sub-title compound as a white solid(3.0 g).

MS (APCI) 463/465 (M+H)⁺

¹H NMR δ (DMSO) 7.90-7.80 (4H, m), 7.49 (1H, d), 7.25 (1H, d), 6.97 (1H,dd), 4.53-4.33 (2H, m), 3.80-3.69 (1H, m), 3.69-3.58 (2H, m), 2.77-2.60(2H, m), 2.38-2.17 (4H, m), 1.94-1.84 (2H, m), 1.85-1.75 (1H, m),1.65-1.50 (3H, m).

Step 2: 4-amino-1-[4-(3,4-dichlorophenoxy)piperidin-1-yl]butan-2-ol

A solution of mixture of2-{4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-3-hydroxybutyl}-1H-isoindole-1,3(2H)-dione(3.00 g) in a mixture of ethanol (75 ml) and 35% aqueous hydrazine (15ml) was heated at reflux 4 h. The mixture was cooled down and thesolvents removed under vacuum. The residue was triturated with warmdichloromethane. The white solid was removed by filtration and thefiltrate dried over sodium sulfate. The mixture was filtered and thesolvent was evaporated to afford the title compound as a yellow oil(2.10 g) which was used without further purification in the next step.

MS (APCI) 333/335 (M+H)⁺

¹H NMR δ (CDCl₃) 7.29 (1H, d), 6.96 (1H, d), 6.76 (1H, dd), 4.40-4.25(1H, m), 3.95-3.85 (1H, m), 3.20-3.00 (2H, m), 2.96-2.79 (1H, m),2.78-2.63 (1H, m), 2.60-2.45 (1H, m), 2.41-2.23 (3H, m), 2.10-1.88 (2H,m), 1.88-1.70 (3H, m), 1.70-1.58 (1H, m).

Preparation 31-Amino-4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]butan-2-ol Step 1:4-(3,4-dichlorophenoxy)-1-(2-oxiran-2-ylethyl)piperidine

A mixture of 4-(3,4-dichlorophenoxy)piperidine (WO 0058305, WO 0177101)(2.00 g), 2-(2-bromoethyl)oxirane (J. Am. Chem. Soc. 1981, 103, 7520-8)(1.36 g) and potassium carbonate (2.2 g) in acetone (20 ml) was stirredat 50° C. for 12 h. The solvent was removed under vacuum. The residuewas partitioned between water and ethyl acetate. The organic layer waswashed with water, brine and dried over magnesium sulfate. The mixturewas filtered and the solvent was evaporated to afford the subtitlecompound as a yellow oil (2.50 g) which was used without furtherpurification in the next step.

MS (APCI) 316/318 (M+H)⁺

¹H NMR δ (CDCl₃) 7.31 (1H, d), 7.00 (1H, d), 6.75 (1H, dd), 4.27 (1H,dquintet), 3.02-2.95 (1H, m), 2.78 (1H, t), 2.77-2.68 (2H, m), 2.57-2.49(3H, m), 2.39-2.24 (2H, m), 2.03-1.94 (2H, m), 1.87-1.75 (2H, m),1.77-1.72 (1H, m), 1.73-1.61 (1H, m).

Step 2: 1-amino-4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]butan-2-ol

In a sealed metal tube, a solution of4-(3,4-dichlorophenoxy)-1-(2-oxiran-2-ylethyl)piperidine (1.00 g) in 7Nammonia in methanol (25 ml) was heated at 70° C. for 12 h. The solventwas removed under vacuum and the residue purified on silicagel (0 to 10%7N ammonia in methanol/dichloromethane) to afford the title compound asa yellow oil (0.55 g).

MS (APCI) 333/335 (M+H)⁺

¹H NMR δ (CDCl₃) 7.31 (1H, d), 6.99 (1H, d), 6.75 (1H, dd), 4.36-4.27(1H, m), 3.79-3.70 (1H, in), 2.93-2.78 (1H, m), 2.76-2.59 (5H, m),2.61-2.50 (1H, m), 2.37-2.27 (1H, m), 2.03-1.90 (2H, m), 1.89-1.76 (2H,m), 1.74-1.61 (1H, m), 1.54-1.46 (1H, m).

Preparation 4(2R)-1-Amino-3-[4-(4-chlorophenoxy)piperidin-1-yl]propan-2-ol

Prepared as described in Preparation 1.

¹H NMR δ (CD₃OD) 7.13 (2H, d), 6.80 (2H, d), 4.26 (1H, septet),3.68-3.59 (1H, m), 2.77-2.65 (2H, m), 2.62 (1H, dd), 2.46 (1H, dd),2.38-2.24 (4H, m), 1.95-1.85 (2H, m), 1.73-1.61 (2H, m).

Preparation 5(2R)-1-Amino-3-[4-(4-chloro-3-fluorophenoxy)piperidin-1-yl]propan-2-ol

Prepared as described in Preparation 1.

MS (ESI) 303/305 (+H)⁺

¹H NMR δ (CD₃OD) 7.32 (1H, t), 6.86 (1H, dd), 6.77 (1H, ddd), 4.40 (1H,quintet), 3.74 (1H, ddd), 2.87-2.75 (2H, m), 2.72 (1H, dd), 2.56 (1H,dd), 2.50-2.37 (4H, m), 2.08-1.95 (2H, m), 1.85-1.72 (2H, m).

Preparation 6(2R)-1-Amino-3-[4-(3,4-difluorophenoxy)piperidin-1-yl]propan-2-ol

Prepared as described in Preparation 1.

MS (ESI) 287 (M+H)⁺

¹H NMR δ (CD₃OD) 7.14 (1H, dt), 6.87 (1H, ddd), 6.75-6.69 (1H, m), 4.35(1H, septet), 3.80-3.71 (1H, m), 2.88-2.75 (2H, m), 2.75 (1H, dd), 2.58(1H, dd), 2.51-2.34 (4H, m), 2.07-1.94 (2H, m), 1.85-1.71 (2H, m).

Preparation 72R)-1-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol Step 1:4-(3,4-dichlorophenoxy)piperidine

4-Hydroxypiperidine (50 g, 494 mmol) was added portionwise to a stirredsuspension of potassium tert-butoxide (110.9 g, 990 mmol) in THF (900ml) at room temperature and under nitrogen. The mixture was heated atreflux and 1,2-dichloro-4-fluorobenzene (98 g, 594 mmol) added dropwiseover 30 minutes. The mixture was sired at reflux for another 1 hour thencooled down to room temperature, diluted with ethyl acetate (500 ml) andwashed with water (500 ml). The organic phase was diluted further withethyl acetate (500 ml) and extracted with 1M hydrochloric acid (200 ml),The aqueous extract was adjusted to pH>10 by addition of a solution ofsodium hydroxide and extracted twice with tert-butylmethyl ether (750ml). The organic extracts were dried over magnesium sulfate, filteredand concentrated under vacuum to yield the sub-title compound as a darkoil which was used as such in the next step.

MS (ESI) 246/248 (M+H)⁺

¹H NMR δ (CDCl₃) 7.31 (1H, d), 7.00 (1H, d), 6.78 (1H, dd), 4.29-4.37(1H, m), 3.15 (2H, dt), 2.75 (2H, td), 1.97-2.03 (2H, m), 1.60-1.70 (2H,m).

Alternative Step 1: 4-(3,4-dichlorophenoxy)piperidine

A thin slurry of 4-hydroxypiperidine (50 g, 494 mmol) in THF (200 ml)was added to a stirred suspension of potassium tert-butoxide (110.9 g,990 mmol) in THF (650 ml) at room temperature and washed in with THF (50ml). The resultant mixture was stirred under nitrogen for 20 minutes.1,2-Dichloro-4-fluorobenzene (98 g, 594 mmol) was added and theresultant mixture heated at reflux for 90 minutes. The reaction mixturewas cooled to room temperature and water (500 ml) added. The layers wereseparated and the solvent removed from the organic fraction. Thematerial was then partitioned between MTBE and 10% aqueous citric acidsolution. The layers separated and the aqueous layer washed with furtherMTBE (2×250 ml). The aqueous phase was basified to pH>10 by addition of10N NaOH solution and the product extracted with iso-propyl acetate(2×30 ml). The organics were washed with brine (300 ml), dried overmagnesium sulfate, filtered and concentrated under vacuum to yield thesub-title compound as a dark oil which was used as such in the next step(109.1 g, 90%).

Step 2:(2S)-1-azido-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol

(2R)-Oxiran-2-ylmethyl 3-nitrobenzenesulfonate (21.1 g, 81.3 mmol) inDMF (300 ml) was treated with triethylamine (22.6 ml, 163.0 mmol)followed by 4-(3,4-dichlorophenoxy)-piperidine (20 g, 81.3 mmol). Themixture was stirred overnight at 60° C. Sodium azide (16 g, 243.9 mmol)was added to the mixture and the reaction was stirred for a further 72h. The solution was carefully concentrated under vacuum and the residuewas diluted with water (600 ml), extracted with ethyl acetate (1500 ml).The organic layer was washed twice with water (500 ml), then brine (200ml) and concentrated under vacuum to afford an oil.

Step 3:(2R)-1-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol

The resulting oil from Step 2 was dissolved in wet tetrahydrofuran (225ml) and was treated with triphenylphosphine (53.3 g, 203 mmol). Thereaction was heated at 60° C. and stirred for 4 h. The solvent wasremoved under vacuum, the residue re-dissolved into 2N hydrochloric acid(1000 ml) and the aqueous layer was extracted with ethyl acetate (3times 700 ml). The aqueous phase was basified with a 2N sodium hydroxidesolution and extracted with dichloromethane (3 times 1000 ml). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated under vacuum. The crude material waspurified by chromatography (8% 7N ammonia in methanol/DCM) to give thetitle compound as a yellow oil (17 g).

MS (APCI) 319/321 (M+H)⁺

¹H NMR δ (CDCl₃) 7.31 (1H, d), 7.00 (1H, d), 6.75 (1H, dd), 4.0 (1H,app. sept), 3.74-3.62 (1H, m), 2.94-2.84 (1H, m), 2.82 (1H, d),2.72-2.61 (1H, m), 2.65 (1H, d), 2.60-2.49 (1H, m), 2.46-2.21 (3H, m),2.06-1.91 (2H, m), 1.90-1.72 (2H, m).

Preparation 8(2R)-1-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol Step1: (2S)-1-Chloro-3-[4-(3,4-chlorophenoxy)piperidin-1-yl]propan-2-ol

(S)-(+)-Epichlorohydrin (3.50 ml, 44.7 mmol) was added to a stirredsolution of 4-(3,4-dichlorophenoxy)piperidine (10.0 g, 40.6 mmol) inethanol (50 ml). After 20 h, water (50 ml) was added. The mixturestirred for a further 2 h then the precipitated solid was collected byfiltration, washed with water and dried under vacuum at 50° C. for 2 hto give the sub-title compound.

MS (ESI) 338/340/342/344 (M+H)⁺

¹H NMR δ (CDCl₃) 7.31 (1H, d), 7.00 (1H, d), 6.75 (1H, dd), 4.28-4.33(1H, m), 3.89-3.96 (1H, m), 3.54-3.62 (3H, m), 2.84-2.92 (1H, m),2.65-2.72 (1H, m), 2.45-2.59 (3H, m), 2.32-2.36 (1H, m), 1.90-2.01 (2H,m), 1.77-1.87 (2H, m).

Step 2:(2R)-1-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol

A solution of sodium hydroxide (1.62 g, 40.6 mmol) in methanol (200 ml)was added to the product of the previous step and the mixture stirredfor 1 h whereupon all solid had dissolved. Aqueous ammonia solution(28%, 80 ml) was added and stirring continued at ambient temperature for3 days. The solution was concentrated in vacuo to a volume of 100 mlthen dissolved in hydrochloric acid (0.5M, 800 ml) and extracted withdiethyl ether (2×200 ml). The aqueous extract was filtered to removeinsoluble impurities then made alkaline by addition of sodium hydroxideand extracted with dichloromethane (4×200 ml) with filtration of thetwo-phase mixture to remove further insoluble impurities. Organicextracts were dried over anhydrous magnesium sulfate, filtered andevaporated under reduced pressure to provide the tide compound as an oil(10.6 g).

MS (APCI) 319/321 (M+H)⁺

¹H NMR δ (CDCl₃) 7.31 (1H, d), 7.00 (1H, d), 6.75 (1H, dd), 4.0 (1H,app. sept.), 3.74-3.62 (1H, m), 2.94-2.84 (1H, m), 2.82 (1H, d),2.72-2.61 (1H, m), 2.65 (1H, d), 2.60-2.49 (1H, m), 2.46-2.21 (3H, m),2.06-1.91 (2H, m), 1.90-1.72 (2H, m).

Preparation 9(2S)-1-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-methylpropan-2-ol

Prepared as described in Preparation 7 (Steps 2 and 3) using[(2R)-2-methyloxiran-2-yl]methyl-3-nitrobenzenesulfonate.

MS (APCI) 333/335 (M+H)⁺

¹H NMR δ (CDCl₃) 7.30 (1H, d), 6.99 (1H, d), 6.75 (1H, dd), 4.38-4.30(1H, m) 3.48 (2H, s), 2.96-2.78 (2H, m), 2.62-2.30 (4H, m), 2.00-1.90(2H, m), 1.85-1.72 (2H, m), 1.25 (3H, s).

Preparation 10(2R)-1-Amino-3-[4-(4-chloro-2-methylphenoxy)-piperidin-1-yl]propan-2-ol

Prepared as described in Preparation 7 (Steps 2 and 3) from4-(4-chloro-2-methylphenoxy)-piperidine.

MS (ESI) 299/301 (M+H)⁺

¹H NMR δ (CD₃OD) 7.12-7.05 (2H, m), 6.87 (1H, d), 4.39 (1H, septet),3.77-3.70 (1H, m), 2.84-2.72 (2H, m), 2.71 (1H, dd), 2.55 (1H, dd),2.50-2.39 (2H, m), 2.40 (1H, d), 2.39 (1H, d), 2.18 (3H, s), 2.04-1.95(2H, m), 1.86-1.75 (2H, m).

Preparation 116-{1-[(2R)-3-Amino-2-hydroxypropyl]piperidin-4-yl}oxy)-2,3-dichlorobenzamide

Step 1: Tert-Butyl4-[2-(aminocarbonyl)-3,4-dichlorophenoxy]piperidine-1-carboxylate

To a stirred solution of tert-butyl4-[3,4-dichlorophenoxy]piperidine-1-carboxylate (7.0 g, 20.3 mmol) indry THF (250 ml) at −70° C. under a nitrogen atmosphere was addeddropwise sec-butyl lithium (18 ml, 1.3M in cyclohexane). The solutionwas stirred a further 30 min. at this temperature then treated withsolid carbon dioxide pellets (excess). The cooling bath was removed andthe mixture stirred vigorously whilst warming to room temperature over 1h. After a further 1 h the solution was concentrated to ca 50 ml volumethen partitioned between aqueous sodium hydrogen carbonate solution anddiethyl ether. The aqueous phase was further washed with diethyl ether(3×), then acidified to pH 4 and extracted with dichloromethane (3×).The combined extracts were dried (magnesium sulphate) and concentrated.Treatment of the crude carboxylic acid (2.5 g, 6.4 mmol) withcarbonyl-1,1-diimidazolide (1.25 g, 7.7 mmol) in dichloromethane (5 ml)at room temperature for 72 h gave the crude imidazolide which wasconcentrated in vacuo, redissolved in ethanol (20 ml) and treated with35% aqueous ammonia (20 ml) in an autoclave at 100° C., for 2 h. Themixture was allowed to cool to room temperature slowly to allowcrystallization of the title compound. The crystalline product wasfiltered and washed with water. Recrystallization from ethanol/watergave the sub-title compound (1.90 g).

MS (APCI) 289/291 (M+H−BOC)⁺

¹H NMR δ (CDCl₃) 7.40 (1H, d), 6.83 (1H, d), 5.91 (1H, s), 5.73 (1H, s),4.52 (1H, m), 3.59 (2H, m), 3.41 (2H, m), 1.86 (4H, m), 1.43 (9H, s).

Step 2: 2,3-dichloro-6-(piperidin-4-yloxy)benzamide

To a stirred solution of tert-butyl4-[-[2-(aminocarbonyl)-3,4-dichlorophenoxy]piperidine-1-carboxylate (1.8g, 4.6 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid(10 ml). After 30 min at room temperature the solution was concentratedin vacuo and partitioned between saturated aqueous sodium hydrogencarbonate solution and dichloromethane. The aqueous was re-extracted afurther three times with dichloromethane and three times with ethyacetate. The combined organic extracts were dried (anhydrous potassiumcarbonate) and concentrated to afford the sub-title compound as a whitesolid (1.15 g).

MS (APCI) 289/291 (M+H)⁺

¹H NMR δ (CD₃OD) 7.49 (1H, d), 7.09 (1H, d), 4.65 (1H, M), 3.15 (2H,2.84 (2H, m), 2.02 (2H, m), 1.82 (2H, m).

Step 3:6-({1-[(2R)-3-amino-2-hydroxypropyl]piperidin-4-yl}oxy)-2,3-dichlorobenzamide

Step a: To a stirred solution of2,3-dichloro-6-(piperidinyloxy)benzamide (1.1 g, 3.8 mmol) indimethylformamide (10 ml) was added triethylamine (1.06 ml. 7.6 mmol)and (2R)-glycidyl-3-nitrobenzenesulfonate (1.0 g, 3.8 mmol) and themixture heated at 60° C. for 3 h. Sodium azide (1.0 g, 15.2 mmol) wasadded and the temperature maintained for a further 48 h The mixture wasconcentrated in vacuo (blast shield) to almost dryness, and the productpartitioned between dichloromethane and aqueous sodium hydrogencarbonate solution. The aqueous layer was reextracted withdichloromethane then with ethyl acetate. The combined organic extractswere dried (anhydrous potassium carbonate) and concentrated in vacuo.

Step b: The product was redissolved in tetrahydrofuran (50 ml) andtreated with water (5 ml) and triphenylphosphine (2.4 g). The mixturewas heated at 60° C. for 4 h, then concentrated in vacuo. The productwas partitioned between ethyl acetate and 1N aqueous hydrochloric acid.The aqueous extracts were washed further with ethyl acetate thenbasified with 48% sodium hydroxide solution to pH 11. The aqueous layerwas extracted with dichloromethane (3×), and the combined organicextracts dried (anhydrous potassium carbonate) and concentrated in vacuoto afford crude amine product which was used without any purification inthe next step (See Example 132).

Preparation 12(R)-1-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-3-methylamino-propan-2-ol

A solution of4-(3,4-dichlorophenoxy)-1-[(2R)-oxiran-2-ylmethyl]piperidine (1 g, 3.31mmol) and methylamine (2.56 ml 40% in H₂O, 33.1 mmol) in ethanol (15 ml)was heated at 60° C. in a sealed vessel for 16 h. The solvent wasevaporated at reduced pressure and the residue purified by flash columnchromatography eluting with 8% 7M ammonia methanol in dichloromethane togive the title compound (875 mg).

MS (APCI) 333/335 (M+H)⁺

¹H NMR δ (CDCl₃) 7.31 (1H, d), 6.99 (1H, d), 6.75 (1H, dd), 4.32-4.26(1H, m), 3.86-3.80 (1H, m), 2.91-2.86 (1H, m), 2.71-2.65 (2H, m), 2.65(1H, dd), 2.56-2.51 (2H, m), 2.54 (1H, dd), 2.48-2.42 (2H, m), 2.46 (3H,s), 2.38-2.27 (3H, m).

Preparation 13(2R)-1-Amino-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl]propan-2-ol

Prepared as described in Preparation 10 using4-(2,4-dichloro-3-methylphenoxy)-piperidine.

MS (APCI) 333/335 (M+H)⁺

¹H NMR δ (CD₃OD) 7.25 (2H, d), 6.94 (2H, d), 4.54-4.37 (1H, m),3.88-3.71 (1H, m), 3.35-3.24 (2H, m), 2.93-2.72 (4H, m), 2.72-2.57 (1H,m), 2.08-1.90 (2H, m), 1.92-1.75 (2H, m).

Preparation 14(2S)-1-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol

Prepared as described in Preparation 7 using(2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate.

MS (ESI) 319/321 (M+H)⁺

¹H NMR δ (CDCl₃) 7.30 (1H, d), 6.99 (1H, d), 6.75 (1H, dd), 4.36-4.24(1H, m), 3.75-3.65 (1H, m), 2.94-2.78 (2H, m), 2.70-2.60 (2H, m),2.59-2.51 (1H, m), 2.41-2.25 (3H, m), 2.03-1.93 (2H, m), 1.87-1.77 (2H,m).

Preparation 15(2R)-1-Amino-2-methyl-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-olStep 1: 2-[[(2R)-2-methyloxiranyl]methyl]-1H-isoindole-1,3(2H)-dione

To a solution of (2S)-(2-methyloxiran-2-yl)methyl3-nitrobenzenesulphonate (1.913 g, 7 mmoles) in dry dimethylformamide(15 ml), was added potassium phthalimide (1.304 g, 7 mmoles). Themixture was stirred at 50° C. for 5 h and then cooled to roomtemperature. The resulting mixture was partitioned between ethyl acetateand water. The aqueous phase was washed with ethyl acetate (2×100 ml)and the combined organic extracts were washed with water (3×100 ml),saturated brine solution, dried over sodium sulfate and concentrated invacuo to leave a crude orange wax. Purification by chromatography(silica, 20% ethyl acetate in iso-hexane) afforded the subtitle compoundas a white solid (0.864 g).

MS (ESI) 189 (M−CO)⁺

¹H NMR δ (CDCl₃) 7.90-7.85 (2H, m), 7.78-7.71 (2H, m), 4.02 (1H, d),3.71 (1H, d), 2.82 (1H, d), 2.62 (1H, d), 1.39 (3H, s).

Step 2 2-[(2R)-3-[4-(3,4-dichlorophenoxy)piperidin1-yl]-2-hydroxy-2-methylpropyl]-1H-isoindole-1,3(2H)-dione

A solution of 4-(3,4-dichlorophenoxy)piperidine (0.985 g, 4 mmoles),2-[[(2R)-2-methyloxiranyl]methyl]-1H-isoindole-1,3(2H)-dione (0.869 g, 4mmoles) and triethylamine (0.809 g, 1.12 ml, 8 mmoles) in ethanol (20ml) was stirred at 50° C. for 5 h. The resulting solution was cooled toroom temperature and concentrated in vacuo to leave a crude yellow gum.Flash chromatography (silica, 2% of 7N methanolic ammonia indichloromethane as eluant) afforded the subtitle compound as a yellowoil (1.24 g).

MS (APCI) 463/465/467 (M+H)⁺

¹H NMR δ (CDCl₃) 7.89-7.85 (2H, m), 7.76-7.72 (2H, m), 7.30 (1H, d),6.98 (1H, d), 6.78 (1H, dd), 4.27-4.21 (1H, m), 3.88 (1H, d), 3.70 (1H,d), 3.43 (1H, bd s), 2.96-2.81 (2H, m), 2.60-2.42 (4H, m), 1.95-1.89(2H, m), 1.80-1.70 (2H, m), 1.15 (3H, s).

Step 3(2R)-1-Amino-2-methyl-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol

To a solution of2-[(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxy-2-methylpropyl]-1H-isoindole-1,3(2H)-dione(278 mg, 0.6 mmoles) in ethanol (5 ml) was added aqueous methylamine(40% wt. solution in water, 6 ml). The mixture was stirred at roomtemperature for 24 h and then concentrated in vacuo to leave a crudeyellow glass. This glass was dissolved in methanol (2 ml), added to anIsolute Flash SCX cartridge (2 g), washed with methanol (25 ml) and 7Nammonia in methanol (25 ml). The methanolic ammonia was concentrated invacuo to give the title compound as a yellow glass (165 mg).

MS (ESI) 333/335/337 (M+H)⁺

¹H NMR δ (CDCl₃) 7.31 (1H, d), 6.99 (1H, d), 6.75 (1H, dd), 4.29-4.21(1H, m), 2.96-2.80 (2H, m), 2.60-2.30 (4H, m), 2.00-1.90 (3H, m),1.85-1.75 (3H, m), 1.13 (3H, s).

Preparation 167-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

1-Oxo-7-sulfo 1,2-dihydroisoquinoline-4-carboxylic acid (5 g) was addedto chlorosulphonic acid (25 ml). The mixture was heated at 100° C. for84 h and then slowly dripped onto ice with sting. The mixture wasfiltered and the residue was washed with water and ether and dried toyield 7-(chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acidas a buff solid (7.5 g).

MS (APCI) 286 (M−H)⁻

¹H NMR δ (DMSO) 11.81 (1H, d), 8.79 (1H, d), 8.48 (1H, d), 8.03 (1H, d),7.96 (1H, dd).

Preparation 177-[(Methylamino)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid

7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1 g)was added to aqueous methylamine (60 ml) and the mixture was stirred for18 h. Concentrated hydrochloric acid was added to acidify the mixture,which was filtered to yield7-[(methylamino)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-1 carboxylicacid as a buff solid (0.84 g).

MS (APCI) 283 (M+H)⁺

¹H NMR δ (DMSO) 12.93 (1H, s), 12.13 (1H, d), 9.03 (1H, d), 8.61 (1H,d), 8.16 (1H, d), 8.12 (1H, dd), 7.65 (1H, q), 2.43 (3H, d).

Preparation 181,2-Dihydro-7-[[(2-hydroxyethyl)amino]sulfonyl]-1-oxo-4-isoquinolinecarboxylicacid

7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1 g)was added to ethanolamine (3 ml) in tetrahydrofuran (3 ml) and themixture was stirred for 18 h. Hydrochloric acid was added to acidify themixture, which was filtered to yield1,2-dihydro-7-[[(2-hydroxyethyl)amino]sulfonyl]-1-oxo-4isoquinolinecarboxylic acid as a white solid.

MS (APCI) 313 (M+H)⁺

¹H NMR δ (DMSO) 12.92 (5H, s), 12.12 (5H, s), 9.01 (6H, d), 8.62 (6H,s), 8.16 (13H, d), 8.13 (13H, dd), 7.81 (6H, t), 4.67 (5H, s), 3.39-3.25(84H, m), 2.81 (13H, q).

Preparation 197-[(Cyclopropylamino)sulfonyl]-1,2-dihydro-1-oxo-4-isoquinolinecarboxylicacid

7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1 g)was added to cyclopropylamine (3 ml) in tetrahydrofuran (20 ml) and themixture was stirred for 18 h. Hydrochloric acid was added to acidify themixture which was filtered to yield7-[(cyclopropylamino)sulfonyl]-1,2-dihydro-1-oxo-isoquinolinecarboxylicacid as a white solid.

MS (APCI) 307 (M−H)⁻

¹H NMR δ (DMSO) 12.93 (1H, s), 12.13 (1H, d), 9.03 (1H, d), 8.65 (1H,d), 8.16 (1H, d), 8.14 (1H, dd), 8.08 (1H, d), 2.13 (1H, dsextet), 0.48(2H, td), 0.39-0.34 (2H, m).

Preparation 207-(Azetidin-1-ylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid

7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1 g)was added to azetidine (0.7 ml) and diisopropylethylamine (0.4 ml) intetrahydrofuran (5 ml) and acetonitrile (5 ml) and the mixture wasstirred for 72 h then evaporated. The solid was crystallised frommethanol then hydrochloric acid was added to acidify the mixture, whichwas filtered to yield7-(azetidin-1-ylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid as a white solid.

MS (APCI) 309 (M+H)⁺

¹H NMR δ (DMSO) 12.99 (1H, s), 12.21 (1H, d), 9.12 (1H, d), 8.54 (1H,d), 8.20 (1H, d), 8.16 (1H, dd), 3.70 (4H, t), 1.99 (2H, quintet).

Preparation 217-(Aminosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1 g)was added to 0.880 ammonia (60 ml) and the mixture was stirred for 18 h.Concentrated hydrochloric acid was added to acidify the mixture, whichwas filtered to yield7-(aminosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid as awhite solid.

MS (APCI) 269 (M+H)⁺

¹H NMR δ (DMSO) 12.91 (1H, s), 12.08 (1H, d), 8.99 (1H, d), 8.68 (1H,d), 8.16 (1H, dd), 8.14 (1H, d), 7.53 (2H, s).

Preparation 227-[(Dimethylamino)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid

7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (0.8g) was added to dimethylamine (15 ml) and the mixture was stirred for 18h. The mixture was acidified with concentrated hydrochloric acid andthen filtered to yield7-[(dimethylamino)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid as a white solid.

MS (APCI) 295 (M−H)⁻

¹H NMR δ (DMSO) 12.96 (1H, s), 12.19 (1H, d), 9.07 (1H, d), 8.50 (1H,d), 8.18 (1H, d), 8.11 (1H, dd), 2.65 (6H, s).

Preparation 237-[(3-Hydroxy-3-methylazetidin-1-yl)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid

7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1g), diisopropylethylamine (3 ml) and 3-methylazetidin-3-ol hydrochloride(0.8 g) in tetrahydrofuran (8 ml) were heated at 55° C. for 3 days. Themixture was acidified with hydrochloric acid and then filtered to yield7-[(3-hydroxy-3-methylazetidin-1-yl)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid as a pale pink solid.

MS (ESI) 337 (M−H)⁻

¹NMR δ (DMSO) 12.99 (1H, s), 12.22 (1H, d), 9.11 (1H, d), 8.53 (1H, s),8.21 (1H, d), 8.16 (1H, dd), 3.61 (2H, d), 3.46 (2H, d), 1.25 (3H, t).

Preparation 244-({1-[(2R)-3-Amino-2-hydroxypropyl]piperidin-4-yl}oxy)-2-chlorobenzonitrile

Step 1: Tert-Butyl 4-(3-chloro-4-cyanophenoxy)piperidine-1-carboxylate

Potassium tert-butoxide (5.57 g, 49.68 mmol) was added to a solution oftert-butyl 4-hydroxypiperidine-1-carboxylate (5.00 g, 24.84 mmol) inglyme (100 ml) and the mixture stirred for 30 min. before addition of 2chloro-4-fluoro-benzonitrile (7.73 g, 49.68 mmol). The reaction wasstirred at room temperature overnight and then partitioned between ethylacetate (250 ml) and water (200 ml). The organic layer was separated,dried over magnesium sulfate and the solvent evaporated. The residue waspurified by flash chromatography eluting with ethyl acetate:isohexane(4:1) to give the subtitle compound as a colourless solid (3.45 g).

MS (ESI) 337 (M+H)⁺

¹H NMR δ (CDCl₃) 1.47 (9H, s), 1.72-1.80 (2H, m), 1.90-1.97 (2H, m),3.37 (2H, ddd), 3.68 (2H, ddd), 4.54 (1H, dquintet), 6.86 (1H, dd), 7.01(1H, d), 7.57 (1H, d).

Step 2:4-({1-[(2R)-3-Amino-2-hydroxypropyl]piperidin-4-yl}oxy)-2-chlorobenzonitrile

To a solution of the tert-butyl4-(3-chloro-4-cyanophenoxy)piperidine-1-carboxylate (2.75 g, 9.09 mmol)in dichloromethane (20 ml) was added trifluoroacetic acid (20 ml) andthe mixture stirred for 90 min. The solvents were evaporated and theresidue azeotroped with toluene (2×20 ml) before dissolving in water (30ml) and addition of sodium hydroxide to bring the solution to pH 11. Thefree base was extracted with DCM (5×100 ml). The organics were combined,dried over sodium sulfate and the solvent removed under reduced pressureto give a thick oil which was dissolved in DMF (30 ml) before additionof (2R)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (2.35 g, 9.09 mmol)and triethylamine (2.54 ml, 18.18 mmol). The mixture was heated at 60°C. for 4 h before addition of sodium azide (1.36 g, 27.27 mmol). Heatingwas continued at 60° C. for a further 72 h. The reaction mixture wascooled and partitioned between water (50 ml) and ethyl acetate (100 ml).The organic layer was separated and the solvent removed under reducedpressure. The residue was dissolved in THF (20 ml) and water (2 ml) andtriphenylphosphine (5.90 g, 22.72 mmol) added The mixture was heated at60° C. for 16 h before dilution with ethyl acetate (100 ml). Thesolution was washed with 1N HCl (50 ml) and the aqueous layer wasseparated and adjusted to pH 11 with sodium hydroxide. The product wasextracted with DCM (4×100 ml). The organics were combined and driedsodium over sulfate and the solvent removed under reduced pressure. Theresidue was purified by flash chromatography to give the title compoundas a pale yellow solid (1.10 g).

MS (ESI) 310 (M+H)⁺

¹H NMR δ (CDCl₃) 7.56 (1H, d), 7.00 (1H, d), 6.85 (1H, dd), 4.42 (1H,septet), 3.73-3.67 (1H, m), 2.93-2.86 (1H, m), 2.86-2.78 (1H, m),2.71-2.62 (2H, m), 2.61-2.55 (1H, m), 2.45-2.30 (3H, m), 2.06-1.96 (2H,m), 1.91-1.79 (2H, m).

Preparation 25(2R)-1-Amino-3-{4-[4-(methylsulfonyl)phenoxy]piperidin-1-yl}propan-2-ol

Prepared as described in Preparation 24 starting from1-fluoro-4-(methylsulfonyl) benzene.

Step 1: tert-Butyl 4-[4-(methylsulfonyl)phenoxy]piperidine-1-carboxylate

¹H NMR δ (CDCl₃) 1.48 (9H, s), 1.74-1.82 (2H, m), 1.91-1.99 (2H, m),3.04 (3H, s), 3.38 (2H, ddd), 3.69 (2H, ddd), 4.57-4.62 (1H, m), 7.02(2H, d), 7.86 (2H, d).

Step 2:(2R)-1-Amino-3-{4-[4-(methylsulfonyl)phenoxy]piperidin-1-yl}propan-2-ol

MS (ESI) 329 (M+H)⁺

¹H NMR δ (CDCl₃) 7.85 (2H, d), 7.01 (2H, d), 4.47 (1H, septet),3.73-3.67 (1H, m), 3.03 (3H, s), 2.95-2.88 (1H, m), 2.86-2.78 (1H, m),2.72-2.62 (2H, m), 2.61-2.55 (1H, m), 2.45-2.30 (3H, m), 2.08-1.98 (2H,m), 1.92-1.81 (2H, m).

Preparation 264-({1-[(2R)-3-Amino-2-hydroxypropyl]piperidin-4-yl}oxy)benzonitrile

Prepared as described in Preparation 24 starting from4-fluorobenzonitrile.

Step 1: tert-Butyl 4-(4-cyanophenoxy)piperidine-1-carboxylate

MS (ESI) 303 (M+H)⁺

¹H NMR δ (CDCl₃) 7.58 (2H, d), 6.95 (2H, d), 4.55 (1H, m), 3.69 (2H,ddd), 3.37 (2H, ddd), 1.97-1.90 (2H, m), 1.80-1.72 (2H, m), 1.47 (9H,s).

Step, 2:4-({1-[(2R)-3-Amino-2-hydroxypropyl]piperidin-4-yl}oxy)benzonitrile

MS (ESI) 276 (M+H)⁺

¹H NMR δ (CDCl₃) 7.57 (2H, d), 6.94 (2H, d), 4.46-4.41 (1H, m),3.74-3.68 (1H, m), 2.94-2.88 (1H, m), 2.83 (1H, dd), 2.73-2.66 (1H, m),2.64 (1H, dd), 2.61-2.55 (1H, m), 2.46-2.30 (3H, m), 2.07-1.97 (2H, m),1.91-1.80 (2H, m).

Preparation 27 tert-Butyl4-[4-chloro-2-(methoxycarbonyl)phenoxy]piperidine-1-carboxylate

Diisopropylazodicarboxylate (5.2 ml, 26.8 mmol) was added dropwise to asolution of 5-chloro-2-hydroxy methylbenzoate (5.0 g, 26.8 mmol),tert-butyl 4-hydroxypiperidine-1-carboxylate (5.4 g, 26.8 mmol) andtriphenylphosphine (7.02 g, 26.8 mmol) in THF (200 ml) at 0° C. Thereaction mixture was allowed to warm to ambient temperature overnightThe solvent was removed under reduced pressure and the residuetriturated with diethyl ether (200 ml). The triphenylphosphineoxide wasfiltered off and the diethyl ether removed under reduced pressure. Theresidue was purified by flash column chromatography eluting with ethylacetate:isohexane (1:9) to give the title compound as a brown oil (8.1g).

MS (ESI) 370 (M+H)⁺

¹H NMR δ (DMSO) 1.47 (9H, s), 1.79-1.92 (4H, m), 3.45-3.54 (2H, m),3.56-3.62 (2H, m), 3.89 (3H, s), 4.54-4.59 (1H, m), 6.92 (1H, d), 7.38(1H, dd), 7.77 (1H, d).

Preparation 282-{[1-(tert-Butoxycarbonyl)piperidin-4-yl]oxy}-5-chlorobenzoic acid

An aqueous solution of 2N sodium hydroxide (20 ml) was added to asolution of tert-butyl 4-[4-chloro-2-(methoxycarbonyl)phenoxy]piperidine-1-carboxylate (8.1 g, 22.0 mmol) in tetrahydrofuran(70 ml) at 45° C. The mixture was stirred vigorously for 3 h thenadjusted to pH 2 with 2N hydrochloric acid. The product was extractedwith ethyl acetate and the organic layer washed repeatedly with wateruntil the washings were pH 6. The organic layer was dried over magnesiumsulfate and evaporated. The residue was azeotroped with toluene to givethe title compound as a colourless solid (7.5 g).

MS (ESI) 356 (M+H)⁺

¹H NMR δ (DMSO) 1.47 (9H, s), 1.79-1.88 (2H, m), 2.03-2.11 (2H, m), 3.30(2H, ddd), 3.77-3.85 (2H, m), 4.72 (1H, m), 7.02 (1H, d), 7.49 (1H, dd),8.12 (1H, d), 10.91 (1H, s).

Preparation 294-(4-Chloro-2-methylcarbamoyl-phenoxy)-piperidine-1-carboxylic acidtert-butyl ester

Bromo-tris-pyrrolidinophosphonium hexafluorophosphate (1.57 g, 3.37mmol) was added to a vigorously stirred mixture of2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}-5-chlorobenzoic acid(1.00 g, 2.8 mmol) and 40% aq methylamine (2 ml) in DCM (10 ml).Stirring was continued for 30 min. before partitioning between 1Nhydrochloric acid (10 ml) and dichloromethane (10 ml). The organic layerwas separated and washed with saturated sodium bicarbonate solution (20ml) and water (20 ml), then dried over sodium sulfate and the solventremoved under reduced pressure. The residue was purified by flash columnchromatography eluting with ethyl acetate:isohexane (1:1) to give thetitle compound as a colourless solid (0.84 g).

MS (ESI) 369 (M+H)⁺

¹H NMR δ (CDCl₃) 8.17 (1H, d), 7.75 (1H, s), 7.35 (1H, dd), 6.91 (1H,d), 4.58 (1H, tt), 3.81-3.71 (2H, m), 3.29 (2H, ddd), 3.00 (3H, d),2.08-1.98 (2H m), 1.48 (9H, s).

Preparation 30 tert-Butyl4-[2-(aminocarbonyl)-4-chlorophenoxy]piperidine-1-carboxylate

Prepared as described in Preparation 29 using aqueous ammonia.

MS (ESI) 355 (M+H)⁺

¹H NMR δ (CDCl₃) 8.18 (1H, d), 7.67-7.61 (1H, m), 7.40 (1H, dd), 6.94(1H, d) 5.83-5.76 (1H, m), 4.61 (1H, m), 3.84-3.76 (2H, m), 3.26 (2H,ddd), 2.09-2.01 (2H, m), 1.82-1.73 (2H, m), 1.47 (9H, s).

Preparation 31 Methyl2-({1-[(2R)-3-amino-2-hydroxypropyl]piperidin-4-yl}oxy)-5-chlorobenzoate

Prepared as described in Preparation 24, Step 2 from tert-butyl4-[4-chloro-2-(methoxycarbonyl)phenoxy]piperidine-1-carboxylate.

MS (ESI) 343 (M+H)⁺

¹H NMR δ (CDCl₃) 7.75 (1H, d), 7.37 (1H, dd), 6.92 (1H, d), 4.46-4.39(1H, m), 3.89 (3H, s), 3.72-3.66 (1H, m), 2.93-2.87 (1H, m), 2.81 (1H,dd), 2.69-2.55 (2H, m), 2.63 (1H, dd), 2.43-2.31 (3H, m), 2.00-1.84(−2H, m), 1.67-1.46 (2H, m).

Preparation 322-({1-[(2R)-3-Amino-2-hydroxypropyl]piperidin-4-yl}oxy)-5-chloro-N-methylbenzamide

Prepared as described in Preparation 24, Step 2 from4-(4-chloro-2-methylcarbamoyl-phenoxy)-piperidine-1-carboxylic acidtert-butyl ester.

MS (ESI) 342 (M+H)⁺

¹H NMR δ (CDCl₃) 8.18 (1H, d), 7.88 (1H, s), 7.34 (1H, dd), 6.91 (1H,d), 4.54-4.48 (1H, m), 3.73-3.67 (1H, m), 3.01 (3H, d), 2.89-2.83 (1H,m), 2.83 (1H, dd) 2.68-2.56 (2H, m), 2.63 (1H, dd), 2.44 (1H, dd),2.39-2.33 (1H, m), 2.34 (1H, dd), 2.13-2.03 (2H, m), 1.94-1.83 (2H, m).

Preparation 332-({1-[(2R)-3-Amino-2-hydroxypropyl]piperidin-4-yl}oxy)-5-chlorobenzamide

Prepared as described in Preparation 24, Step 2 from tert-butyl4-[2-(aminocarbonyl)-4-chlorophenoxy]piperidine-1-carboxylate.

MS (ESI) 328 (M+H)⁺

¹H NMR δ (CDCl₃) 8.19 (1H, d), 7.75 (1H, s), 7.39 (1H, dd), 6.93 (1H,d), 5.85 (1H, s), 4.56-4.48 (1H, m), 3.73-3.67 (1H, m), 2.93-2.86 (1H,m), 2.83 (1H, dd), 2.73-2.66 (1H, m), 2.63 (1H, dd), 2.61-2.54 (1H, m),2.44 (1H, dd), 2.37-2.30 (1H, m), 2.35 (1H, dd), 2.15-2.05 (2H, m), 1.90(2H, dtd).

Preparation 34 Tert-Butyl4-{3,4-dichloro-2-[(cyclopropylamino)carbonyl]phenoxy}piperidine-1-carboxylate

A solution of tert-butyl4-[3,4-dichloro-2-(1H-imidazol-1-ylcarbonyl)phenoxy]piperidine-1-carboxylate(described in Preparation 11 step 1) (2.0 g, 4.5 mmol) incyclopropylamine (12 ml) was heated at 50° C. for 14 h. The solution wasconcentrated in vacuo then partitioned between ethyl acetate and 1Naqueous hydrochloric acid. The organics were dried over magnesiumsulfate and concentrated in vacuo. Crystallization fromdichloromethane:isohexane gave the title compound as a white solid (0.64g).

MS (ESI) 429/431 (M+H)⁺

¹H NMR δ (DMSO) 8.46 (1H, d), 7.56 (1H, d), 7.17 (1H, d), 4.68 (1H, m),3.42-3.27 (4H, m), 2.74 (1H, m), 1.78 (2H, m), 1.55 (2H, m), 0.68 (2H,m), 0.44 (2H, m).

Preparation 356-{[1-(3-Amino-2-hydroxypropyl)piperidin-4-yl]oxy}-2,3-dichloro-N-cyclopropylbenzamide

Prepared as described in Preparation 24, Step 2 following Preparation34.

MS (ESI) 402 (M+H)⁺

¹H NMR δ (CDCl₃) 7.35 (1H, d), 6.78 (1H, d), 5.82 (1H, s), 4.40-4.33(1H, m), 3.68 (1H, tt), 2.92-2.85 (2H, m), 2.85-2.77 (2H, m), 2.81 (1H,dd), 2.62 (1H, dd), 2.42-2.29 (3H, m), 2.00-1.89 (2H, m), 1.88-1.79 (2H,m), 0.89 (2H, td), 0.66-0.62 (2H, m).

Preparation 36 Tert-Butyl4-(3,4-dichloro-2-(chlorosulfonyl)phenoxy]piperidine-1-carboxylate

To a stirred solution of tert-butyl4-[3,4-dichlorophenoxy]piperidine-1-carboxylate (10.0 g, 28.9 mmol) indry THF (400 ml) at −70° C. under a nitrogen atmosphere was addeddropwise sec-butyl lithium (26.7 ml, 1.3M in cyclohexane). The solutionwas stirred a further 15 min. at this temperature and then sulfurdioxide was bubbled through the mixture for 10 min. The cooling bath wasremoved and the mixture warmed to room temperature over 1 h.N-Chlorosuccinimide (4.63 g, 35 mmol) was added and the mixture stirredat room temperature for 72 h. The solution was concentrated in vacuo andpartitioned between ethyl acetate and 1N aqueous hydrochloric acid. Theorganic extracts were dried (magnesium sulphate) and concentrated.Chromatography on silica (ethyl acetate: isohexane/1:3) gave the titlecompound (2.40 g).

MS (ESI) 445 (M+H)⁺

¹H NMR δ (DMSO) 7.45 (1H, d), 7.03 (1H, d), 4.65 (1H, m), 3.59 (2H, m),3.33 (3H, s), 1.66 (4H, m), 1.40 (9H, s).

Preparation 37 2,3-Dichloro-6-(piperidin-4-yloxy)benzenesulfonamide

tert-Butyl-4-[3,4-dichloro-2-(chlorosulfonyl)phenoxy]piperidine-1-carboxylate(0.80 g, 1.8 mmol) was dissolved in 7N ammonia in methanol and stirredat room temperature for 20 min. The solution was concentrated in vacuoand then azeotroped once with toluene. The residue was redissolved indichloromethane:trifluoroacetic acid/1:1 (20 ml) and stirred at roomtemperature for 15 minutes. The solution was concentrated in vacuo, thenpartitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The aqueous was reextacted with ethyl acetate (4times), and the combined organics dried over anhydrous potassiumcarbonate. Concentration in vacuo afforded the title compound as a whitepowder (0.54 g).

MS (ESI) 325/327 (M+H)⁺

¹H NMR δ (DMSO) 7.74 (1H, d), 7.34 (1H, d), 4.66 (1H, m), 2.96 (2H, m),2.55 (2H, m), 1.91 (2H, m), 1.63 (2H, m).

Preparation 382,3-Dichloro-N-methyl-6-(piperidin-4-yloxy)benzenesulfonamide

tert-Butyl4-[3,4-dichloro-2-chlorosulfonyl)phenoxy]piperidine-1-carboxylate (0.70g, 1.8 mmol) was dissolved in 40% aqueous methylamine in water (10 ml)and methanol (10 ml) and stirred at room temperature for 30 min. Thesolution was concentrated in vacuo and then azeotroped with toluene (4times). The residue was redissolved in dichloromethane/trifluoroaceticacid (1:1) (20 ml) and stirred at room temperature for 15 minutes. Thesolution was concentrated in vacuo, then partitioned between ethylacetate and saturated aqueous sodium hydrogen carbonate solution. Theaqueous was reextracted with ethyl acetate (4 times), and the combinedorganics dried over anhydrous potassium carbonate. Concentration invacuo afforded the title compound as a white powder (0.69 g).

MS (ESP) 339/341 (M+H)⁺

¹H NMR δ (DMSO) 7.76 (1H, d), 7.35 (1H, d), 4.64 (1H, m), 2.96 (2H, m),2.54 (3H, s), 2.54 (2H, m), 1.90 (2H, m), 1.61 (2H, m).

Preparation 392,3-Dichloro-N-cyclopropyl-6-(piperidin-4-yloxy)benzenesulfonamide

tert-Butyl4-[3,4-dichloro-2-(chlorosulfonyl)phenoxy]piperidine-1-carboxylate (0.70g, 1.8 mmol) was dissolved in cyclopropylamine (8 ml) and stirred atroom temperature for 30 min. The solution was concentrated in in vacuoand then azeotroped with toluene (4 times). The residue was redissolvedin dichloromethane: trifluoroacetic acid/1:1 (20 ml) and stirred at roomtemperature for 15 min. The solution was concentrated in vacuo, thenpartitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The aqueous was reextracted with ethyl acetate (4times), and the combined organics dried over anhydrous potassiumcarbonate. Concentration in vacuo afforded the title compound as a whitepowder (0.70 g).

MS (ESI) 365/367 (M+H)⁺

¹H NMR δ (DMSO) 7.78 (1H, d), 7.36 (1H, d), 4.65 (1H, m), 2.97 (2H, m),2.55 (2H, m), 2.27 (1H, m), 1.89 (2H, m), 1.63 (2H, m), 0.49 (4H, m);

Preparation 406-({1-[(2R)-3-Amino-2-hydroxypropyl]piperidin-4-yl}oxy)-2,3-dichlorobenzenesulfonamide

Prepared as described in Preparation 7 (Steps 2 and 3) followingPreparation 37.

MS (ESI) 398/400 (M+H)⁺

Preparation 416-({1-(2R)-3-Amino-2-hydroxypropyl]piperidin-4-yl}oxy)-2,3-dichloro-N-methylbenzenesulfonamide

Prepared as described in Preparation 7 (Steps 2 and 3) followingPreparation 38.

MS (ESI) 412/414 (M+H)⁺

Preparation 426-({1-[(2R)-3-Amino-2-hydroxypropyl]piperidin-4-yl}oxy)-2,3-dichloro-N-cyclopropylbenzenesulfonamide

Prepared as described in Preparation 7 (Steps 2 and 3) followingPreparation 39.

MS (ESI) 438/440 (M+H)⁺

Preparation 437-(Methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

To a solution of sodium bicarbonate (500 mg) and sodium sulfite (353 mg)in 4 ml of water at 0° C. was added portionwise the7-chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (seePreparation 16) (400 mg). The reaction was warmed to room temperatureand then heated at 80° C. for 2 h. The reaction was cooled to 0° C. andacidified to pH-1 with concentrated hydrochloric acid. The suspensionwas diluted with 4 ml of water and stirred for 15 minutes at 0° C. thenfiltered under nitrogen. The solid was washed twice with water and wasadded to a degassed aqueous solution (3 ml) of potassium hydrogencarbonate (280 mg) at 45° C. Ethanol was then slowly added until thesolution became slightly cloudy. Iodomethane (262 μl) was then added andthe reaction refluxed (45-50° C.) for 5 h. The reaction was concentratedunder vacuum, extracted with ethyl acetate and the aqueous phaseacidified with concentrated hydrochloric acid. The reaction was stirredat 0° C. for 30 min. and the solid collected by filtration thenrecrystalised from acetone to yield the title compound as a white solid(325 mg).

MS (ESI) 266 (M−H)⁻

¹H NMR δ (DMSO) 12.97 (1H, bs), 12.19 (1H, d), 9.07 (1H, d), 8.70 (1H,d), 8.27 (1H, dd), 8.19 (1H, d), 3.30 (3H, s).

Preparation 44 6-(Methylsulphonyl)-1H-indole-3-carboxylic acid

Prepared as described in Preparation 43 following Preparation 16 usingindole-3-carboxylic acid.

MS (ES) 238 (M−H)⁻

¹H NMR δ (DMSO) 12.34 (1H, bd s), 12.29 (1H, v bd s), 8.31 (1H, s), 8.21(1H, d), 8.03 (1H, d), 7.69 (1H, dd), 3.20 (1H, d).

Preparation 45 6-Fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

Prepared following literature procedures: Liebigs Annalen der Chemie,1981, 5, 819-27 and Chemical & Pharmaceutical Bulletin, 1983, 31,1277-82.

Step 1: Dimethyl [5-fluoro-2-methoxycarbonyl)phenyl]malonate

(Prepared according to U.S. Pat. No. 5,189,168)

To a rapidly stirred suspension of 2-bromo-4-fluorobenzoic acid (4.5 g)and copper(I) bromide (175 mg) in 25 ml of dimethylmalonate at 0° C. wasadded portionwise sodium hydride (60% in mineral oil, 1.3 g). After 10min., the reaction warmed to room temperature and stirred for 30 minutesat room temperature then heated at 70° C. for 2 h. The solidifiedreaction was then diluted with water (80 ml) and was extracted withdiethyl ether (3×50 ml). The aqueous layer was acidified withconcentrated hydrochloric acid and extracted with ethyl acetate (3×100).The combined organic layers were dried over magnesium sulfate, filtered,concentrated under vacuum and the crude material recrystallised fromdiethyl ether/iso-hexane to yield the sub-title compound as a whitesolid (1.9 g).

¹H NMR δ (DMSO) 13.36 (1-H, bs), 8.05 (1H, dd), 7.35 (1H, ddd), 7.14(1-H, dd), 5.08 (1H, s), 3.70 (6H, s).

Step 2: 2-(Carboxymethyl)-4-fluorobenzoic acid

A suspension of dimethyl [5-fluoro-2-(methoxycarbonyl)phenyl]malonate(1.80 g) in concentrated hydrochloric acid (25 ml) was heated at 110° C.for 48 h. The reaction was cooled and the subtitle compound collected asa white solid by filtration (1.0 g).

MS (ESI) 197 (M−H)⁻

¹H NMR δ (DMSO) 7.97 (1H, dd), 7.24 (1H, dd), 7.20 (1H, dd), 3.96 (2H,s).

Step 3: (4Z)-6-Fluoro (methoxymethylene)-1H-isochromene-1,3(4)-dione

2-(Carboxymethyl)-4-fluorobenzoic acid (1.40 g) in a mixture of aceticacid (3 ml) and trimethylorthoformate (1 ml) was heated at 110° C. for 3h. During this time the methyl acetate generated was distilled off. Whenfinished, the reaction was cooled to 0° C. The white solid was collectedby filtration and was washed with cold water and methanol (1.32 g).

MS (ESI) 207 (M−Me)⁻

Step 4: Methyl 6-fluoro-1-oxo-1H-isochromene-4-carboxylate

To a suspension of(4Z)-6-fluoro-4-(methoxymethylene)-1H-isochromene-1,3(4H)-dione (1.30 g)in methanol (20 ml) was slowly added sulfuric acid (1.5 ml). The mixturewas heated at 40-50° C. for 3 h. As the reaction proceeded the sub-titlecompound crystallized out. The reaction was cooled to room temperatureand a white solid was collected by filtration and washed with coldmethanol.

MS (ESI) 222 (M+H)⁺

¹H NMR δ (DMSO) 8.49 (1H, s), 8.30 (1H, dd), 8.25 (1H, dd), 7.56 (1H,td), 3.87 (3H, s).

Step 5: Methyl 6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylate

A mixture of methyl 6-fluoro-1-oxo-1H-isochromene-4-carboxylate (1.53 g)and ammonium acetate (2.5 g) in 4 ml of glacial acetic acid was heatedat 80° C. for 16 h. The reaction was cooled to 40° C., diluted with 8 mlof water and the solid collected by filtration (1.38 g).

MS (ESI) 220 (M−H)⁻

¹H NMR δ (DMSO) 12.00 (1H, s), 8.46 (1H, dd), 8.32 (1H, dd), 8.10 (1H,s), 7.44 (1H, td), 3.83 (3H, s).

Step 6: 6-Fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

To a solution of methyl6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylate (1.3 g) in methanol(3 ml) was added a aqueous solution (3 ml) of sodium hydroxide (1 g) andthe reaction mixture was heated at 80° C. for 3 h. The reaction wascooled to 20° C. and carefully acidified with concentrated hydrochloricacid. The white precipitate was isolated by filtration, washed withwater and methanol to yield the title compound (1.16 g)

MS (ESI) 206 (M−H)⁻

¹H NMR δ (DMSO) 12.85 (1H, s), 11.91 (1H, d), 8.58 (1H, dd), 8.31 (1H,dd), 8.09 (1H, d), 7.41 (1H, td).

Preparation 46 7-Fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

Prepared following literature procedures: Liebigs Annalen der Chemie,1981, 5, 819-27 and Chemical & Pharmaceutical Bulletin, 1983, 31,1277-82.

Step 1: Dimethyl [4-fluoro-2-(methoxycarbonyl)phenyl]malonate

Prepared as described in Preparation 45, Step 1 using2-bromo-5-fluorobenzoic acid.

MS (ESI) 269/237 (M−H)⁻

¹H NMR δ (DMSO) 7.70 (1H, dd), 7.49 (1H, td), 7.39 (1H, dd), 5.71 (1H,s), 3.68 (6H, s).

Step 2: 2-(Carboxymethyl)-5-fluorobenzoic acid

Prepared as described in Preparation 45, Step 2 using dimethyl(4-fluoro-2-(methoxycarbonyl)phenyl]malonate.

MS (ESI) 197 (M−H)⁻

¹H NMR δ (DMSO) 7.81-7.74 (1H, m), 7.62 (1H, dd), 7.41-7.35 (1H, m),3.92 (2H, s).

Step 3: Methyl 7-fluoro-1-oxo-1-H-isochromene-4-carboxylate

Prepared as described in Preparation 45, Steps 3 and 4 using2-carboxymethyl)-5-fluorobenzoic acid.

MS (ESI) 223 (M+H)⁺

¹H NMR δ (DMSO) 8.60 (1H, dd), 8.42 (1H, s), 7.95 (1H, dd), 7.86 (1H,ddd), 3.87 (3H, s).

Step 4: Methyl 7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylate

Prepared as described in Preparation 45, Step 5 using methyl7-fluoro-1-oxo-1H-isochromene-4-carboxylate.

MS (ESI) 221 (M−H)⁻

¹H NMR δ (DMSO) 12.04 (1H, s), 8.82 (1H, dd), 8.03 (1H, s), 7.91 (1H,dd), 7.73 (1H, td), 3.83 (3H, s).

Step 5: 7-Fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

Prepared as described in Preparation 45, Step 6 using, methyl7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylate.

MS (ESI) 206 (M−H)⁻

¹H NMR δ (DMSO) 12.81 (1H, s), 12.00 (1H, d), 8.93 (1H, dd), 8.02 (1H,d), 7.90 (1H, dd), 7.71 (1H, td).

Preparation 476-(Methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

Prepared following literature procedures: Liebigs Annalen der Chemie,1981, 5, 819-27 and Chemical & Pharmaceutical Bulletin, 1983, 31,1277-82.

Step 1:2-[2-Ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]44-methylsulfonyl)benzoic acid

Prepared following literature procedure: Journal of Organic Chemistry,1998, 63, 4116-4119.

To a very rapidly stirred suspension of2-chloro-4-(methylsulfonyl)benzoic acid (10.0 g) and copper(I) bromide(0.1 g) in 50 ml of diethylmalonate at 20° C. was added portionwisesodium ethoxide (10.0 g). The reaction was stirred for 30 min. at roomtemperature then heated at 90° C. for 36 h. The slurry was diluted withwater (200 ml), aqueous ammonia was added (3 ml) and the mixtureextracted with diethyl ether (3×100 ml). The aqueous layer was acidifiedwith concentrated hydrochloric acid and extracted with ethyl acetate(3×100 ml). The combined organic layers were dried over magnesiumsulfate, filtered and concentrated under vacuum.

MS (ESI) 357/311 (M−H)⁻

¹H NMR δ (CD₃OD) 8.28 (1H, d), 8.06 (1H, dd), 7.99 (1H, d), 5.78 (1H,s), 4.20 (4H, q), 3.19 (3H, s), 1.28 (6H, t).

Step 2: 2-(Carboxymethyl)-4-(methylsulfonyl)benzoic acid

Prepared following literature procedure: Journal of Organic Chemistry,1998, 63, 4116-4119.

The crude material of Step 1 was dissolved in methanol (200 ml) and asolution (200 ml) of sodium hydroxide (13 g) slowly added. The reactionwas stirred at room temperature for 3 h. The methanol was removed undervacuum. The aqueous layer was extracted with diethyl ether (3×100 ml),acidified with concentrated hydrochloric acid, saturated with sodiumchloride and extracted with ethyl acetate (3×100 ml). The combinedorganic layers were dried over magnesium sulfate, filtered, concentratedto one third volume and heated at 65° C. for 3 h to completedecarboxylation. A solid formed which was collected by filtration (7.1g).

MS (ESI) 257/213 (M−H)⁻

¹H NMR δ (DMSO) 8.10 (1H, d), 7.95 (1H, d), 7.93 (1H, dd), 4.07 (2H, s),3.28 (3H, s).

Step 3:(4Z)-4-(methoxymethylene)-6-(methylsulfonyl)-1H-isochromene-1,3(4H)-dione

Prepared as described in Preparation 45, Step 3 using2-(carboxymethyl)-4-(methylsulfonyl)benzoic acid.

MS (ESI) 267 (M−Me)⁻

¹H NMR δ (DMSO) 8.68 (1H, d), 8.32 (1H, d), 8.31 (1H, s), 7.98 (1H, dd),4.36 (3H, s), 3.46 (3H, s).

Step 4: Methyl 6-methylsulfonyl)-1-oxo-1H-isochromene-4-carboxylate

Prepared as described in Preparation 45, Step 4 using(4Z)-4-(methoxymethylene)-6-(methylsulfonyl)-1H-isochromene-1,3(4H)-dione.

¹H NMR δ (DMSO) 9.08 (1H, d), 8.56 (1H, s), 8.44 (1H, d), 8.18 (1H, dd),3.89 (3H, s), 3.34 (3H, s).

Step 5: Methyl 6-(methylsulfonyl)1-oxo-1,2-dihydroisoquinoline-4-carboxylate

Prepared as described in Preparation 45, Step 5 using methyl6-(methylsulfonyl)-1-oxo-1H-isochromene-4-carboxylate.

MS (ESI) 280 (M−H)⁻

¹H NMR δ (DMSO) 12.23 (1H, s), 9.35 (1H, d), 8.47 (1H, d), 8.17 (1H, s),8.06 (1H, dd), 3.86 (3H, s), 3.78 (3H, s).

Step 6: 6-(Methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid

Prepared as described in Preparation 45, Step 6 using methyl6-methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylate.

MS (ESI) 266 (M−H)⁻

¹H NMR δ (DMSO) 12.99 (1H, s), 12.14 (1H, d), 9.45 (1H, d), 8.46 (1H,d), 8.15 (1H, d), 8.04 (1H, dd), 3.30 (3H, s).

Preparation 48(2R)-1-Amino-3-{4-[3,4-dichloro-2-methylsulfonyl)phenoxy]piperidin-1-yl}propan-2-ol

Step 1: Tert-butyl4-[3,4-dichloro-2-(methylsulfonyl)phenoxy]piperidine-1-carboxylate

To a stirred solution of tert-butyl4-[3,4-dichlorophenoxy]piperidine-1-carboxylate (10.0 g, 28.9 mmol) indry THF (400 ml) at −70° C. under a nitrogen atmosphere was addeddropwise sec-butyl lithium (26.7 ml, 1.3M in cyclohexane). The solutionwas stirred a further 15 min. at this temperature and then was treatedwith dimethyldisulfide (3.9 ml, 43 mmol). The solution was stirred atthis temperature for 30 min. and then the cooling bath removed and themixture stirred vigorously whilst warming to −30° C. over 30 mm.Saturated aqueous ammonium chloride solution (5 ml) was added and themixture concentrated to ca 30 ml volume and partitioned between waterand ethyl acetate. The organic extracts were dried over magnesiumsulphate and concentrated. Treatment of the crude residue withmeta-chloroperbenzoic acid (13.3 g, 57-86%) in dichloromethane (200 ml)at room temperature for 14 h gave the crude sulfone. The solution wasshaken with sodium metabisulfite solution, then the organics dried overmagnesium sulfate and concentrated in vacuo. Chromatography on silica(ethyl acetate: isohexane) gave the subtitle compound (0.65 g).

MS (ESI) 424/426 (M+H)⁺

¹H NMR δ (DMSO) 7.88 (1H, d), 7.42 (1H, d), 4.92 (1H, m), 3.52 (2H, m),3.32 (3H, s), 3.36-3.27 (2H, m), 1.90 (2H, m), 1.69 (2H, m), 1.40 (9H,s).

Step 2:(2R)-1-Amino-3-{4-[3,4-dichloro-2-(methylsulfonyl)phenoxy]piperidin-1-yl}propan-2-ol

Prepared as described in Preparation 24, Step 2 from tert-butyl4-[3,4-dichloro-2-(methylsulfonyl)phenoxy]piperidine-1-carboxylate.

MS (ESI) 397/399 (M+H)⁺

¹H NMR δ (CDCl₃) 7.66 (1H, d), 6.94 (1H, d), 4.60-4.53 (1H, m),3.73-3.67 (1H, m), 3.33 (3H, s), 3.02-2.96 (1H, m), 2.81 (1H, dd),2.79-2.73 (1H, m), 2.64-2.56 (1H, m), 2.63 (1H, dd), 2.43-2.32 (3H, m),2.11-1.91 (4H, m).

Preparation 49 8-Fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acidStep 1: 2-(Carboxymethyl)-6-fluorobenzoic acid

Prepared as described in Preparation 45, Step 1 and 2 using2-bromo-6-fluorobenzoic acid.

MS (ESI) 197 (M−H)⁻

¹H NMR δ (DMSO) 7.46 (1H, td), 7.20 (1H, dd), 7.18 (1H, d), 3.77 (2H,s).

Step 2: (4Z)-8-Fluoro-4-(methoxymethylene)-1H-isochromene-1,3(4H)-dione

Prepared as described in Preparation 45, Step 3 using2-(carboxymethyl)-6-fluorobenzoic acid.

MS (ESI) 207 (M−Me)⁻

Step 3: Methyl 8-fluoro-1-oxo-1H-isochromene-4-carboxylate

Prepared as described in Preparation 45, Step 4 using(4Z)-8-fluoro-4-(methoxymethylene)-1H-isochromene-1,3(4)-dione.

MS (ESI) 222 (M+H)⁺

¹H NMR δ (DMSO) 8.42 (1H, s), 8.34 (1H, d), 7.96 (1H, td), 7.50 (1H,dd), 3.86 (2H, s).

Step 4: Methyl 8-fluoro-1-oxo-1,2-dihydroisoquoline-4-carboxylate

Prepared as described in Preparation 45, Step 5 using methyl8-fluoro-1-oxo-1H-isochromene-4-carboxylate.

MS (ESI) 220 (M−H)⁻

¹H NMR δ (DMSO) 11.86 (1H, s), 8.57 (1H, d), 8.03 (1H, s), 7.80 (1H,td), 7.30 (1H, dd), 3.82 (3H, s).

Step 5: 8-Fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid

Prepared as described in Preparation 45, Step 6 using methyl8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylate.

MS (ESI) 206 (M−H)⁻

¹H NMR δ (DMSO) 12.75 (19H, s), 11.76 (19H, d), 8.69 (2H, d), 8.02 (23H,d 7.78 (24H, td), 7.29 (22H, dd).

EXAMPLE 1N-{(2-R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(methylsulfonyl)benzamide

A mixture of 2-(methylsulphonyl)benzoic acid (0.063 g),(2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1g) and N,N-diisopropylethylamine (0.1 ml) in dry dimethylformamide (3ml) was cooled to 0° C. with stirring.2-(1H-9-Azabenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (0.13 g) was added and the mixture was stirred at 0°C. for 1-2 h. Saturated sodium bicarbonate solution (10 ml) was added.The mixture was extracted with ethyl acetate. The organic layer wasseparated and washed with brine and dried over sodium sulphate. Themixture was filtered and the solvent was evaporated. The resulting oilwas purified by normal phase chromatography usingmethanol/dichloromethane as eluent, and by reverse phase HPLC usingacetonitrile and 0.1% aqueous ammonium acetate as eluent, to give thetitle compound as a white solid (0.055 g).

MS (APCI) 501/503 (M+H)⁺

¹H NMR δ (DMSO) 8.57 (1H, t), 7.96 (1H, dd), 7.78 (1H, td), 7.69 (1H,td), 7.57 (1H, dd), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.48-4.37(1H, m), 3.85-3.74 (1H, m), 3.40-3.25 (1H, m), 3.37 (3H, s), 3.26-3.13(1H, m), 2.83-2.69 (2H, m), 2.37-2.26 (3H, m), 1.95-1.84 (2H, m),1.65-1.50 (2H, m).

EXAMPLE 2N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4-(methylsulfonyl)benzamide

Prepared as described in Example 1 from(2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1g) and 4-(methylsulphonyl)benzoic acid (0.063 g). Title compoundobtained as white solid (0.038 g).

MS (APCI) 501/503 (M+H)⁺

¹H NMR δ (DMSO) 8.69 (1H, t), 8.05 (4H, dd), 7.9 (1H, d), 7.25 (1H d),6.98 (1H, dd), 4.76 (1H, brs), 4.43 (1H, mult), 3.86-3.78 (1H, m), 3.43(1H, dt), 3.26 (3H, s), 3.20 (1H, dd), 2.79-2.67 (2H, m), 2.41-2.24 (4H,m), 1.95-1.85 (2H, m), 1.66-1.54 (2H, m).

EXAMPLE 32-Chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4-(methylsulfonyl)benzamide

Prepared as described in Example 1 using(2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1g) and 3-(methylsulfonyl)benzoic acid (0.074 g). Title compound obtainedas white solid (0.033 g).

MS (APCI) 535/537 (M+H)⁺

¹H NMR δ (DMSO) 8.60 (1H, t), 8.03 (1H, d), 7.93 (1H, dd), 7.70 (1H, d),7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.70 (1H, brs), 4.47-4.39(1H, m), 3.82-3.74 (1H, m), 3.41-3.31 (1H, m), 3.29 (3H, s), 3.23-3.15(1H, m), 2.80-2.69 (2H, m), 2.44-2.25 (4H, m), 1.96-1.86 (2H, m),1.65-1.54 (2H, m).

EXAMPLE 44-Amino-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-methoxybenzamide

Prepared as described in Example 1 from(2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1g) and 4-amino-3-methoxybenzoic acid (0.052 g). Title compound obtainedas white solid (0.053 g).

MS (APCI) 468/470 (M+H)⁺

¹H NMR δ (DMSO) 8.05 (1H, t), 7.49 (1H, d), 7.31-7.27 (2H, m), 7.25 (1H,d) 6.98 (1H, dd), 6.60 (1H, d), 5.23 (2H, s), 4.74 (1H, brs), 4.47-4.38(1H, m), 3.80 (3H, s) 3.81-3.73 (1H, m), 3.38-3.30 (1H, m), 3.18-3.09(1H, m), 2.80-2.65 (2H, m), 2.36 (2H, dd), 2.32-2.22 (2H, m), 1.95-1.86(2H, m), 1.66-1.54 (2H, m).

EXAMPLE 5N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-(methylsulfonyl)benzamide

Prepared as described in Example 1 from(2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1g) and 3-(methylsulfonyl)benzoic acid (0.063 g). Title compound obtainedas white solid (0.017 g).

MS (APCI) 501/503 (M+H)⁺

¹H NMR δ (DMSO) 8.74 (1H, t), 8.39 (1H, t), 8.18 (1H, dt), 8.07 (1H,ddt), 7.76 (1H, t), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.77 (1H,brs), 4.47-4.39 (1H, m), 3.86-3.78 (1H, m), 3.45 (1H, dt), 3.26 (3H, s),3.24-3.14 (1H, m), 2.80-2.66 (2H, m), 2.41-2.24 (4H, m), 1.95-1.86 (2H,m), 1.65-1.54 (2H, m).

EXAMPLE 6N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-(methylsulfonyl)thiophene-2-carboxamide

Prepared as described in Example 1 from(2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1g) and 5-(methylsulfonyl)thiophene-2-carboxylic acid (0.065 g). Titlecompound obtained as white solid (0.039 g).

MS (APCI) 507/509 (M+H)⁺

¹H NMR δ (DMSO) 8.85 (1H, t), 7.84 (2H, dd), 7.49 (1H, d), 7.26 (1H, d),6.98 (1H, dd), 4.80 (1H, brs), 4.47-4.39 (1H, m), 3.83-3.75 (1H, m),3.45-3.38 (1H, m), 3.38 (3H, s), 3.18-3.09 (1H, m), 2.79-2.66 (2H, m),2.37-2.22 (4H, m), 1.95-1.85 (2H, m), 1.65-1.53 (2H, m).

EXAMPLE 7N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}quinoline-6-carboxamide

Prepared as described in Example from(2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1g) and quinoline-6-carboxylic acid (0.054 g). Title compound obtained aswhite solid (0.032 g).

MS (APCI) 474/476 (M+H)⁺

¹H NMR δ (DMSO) 8.98 (1H, dd), 8.68 (1H, t), 8.52 (1H, d), 8.47 (1H,dd), 8.19 (1H, dd), 8.08 (1H, d), 7.61 (1H, dd), 7.49 (1H, d), 7.24 (1H,d), 6.97 (1H, dd), 4.78 (1H, brs), 4.48-4.39 (1H, m), 3.90-3.82 (1H, m),3.46 (1H, dt), 3.31-3.23 (1H, m), 2.82-2.70 (2H, m), 2.45-2.25 (4H, m),1.96-1.87 (2H, m), 1.67-1.55 (2H, m).

EXAMPLE 8N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxamideacetate salt

Prepared as described in Example 1 from(2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1g) and 2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxylic acid (0.061 g).Title compound obtained as acetate salt, a white solid (0.10 g).

MS (APCI) 496/498 (M+H)⁺

¹H NMR δ (DMSO) 8.36 (1H, t), 8.05 (1H, d), 7.78 (1H, dd), 7.49 (1H, d),7.25 (1H, d), 7.15 (1H, d), 6.98 (1H, dd), 4.47-4.40 (1H, m), 3.80 (1H,quintet), 3.38 (1H, dt), 3.22-3.14 (1H, m), 2.80-2.67 (2H, m), 2.41-2.25(4H, m), 1.95-1.86 (2H, m), 1.91 (3H, s), 1.66-1.54 (2H, m).

EXAMPLE 9N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-fluoroimidazo[1,2-a]pyridine-2-carboxamide

Prepared as described in Example 1 from(2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1g) and 6-fluoroimidazo[1,2-a]pyridine-2-carboxylic acid (0.056 g). Titlecompound obtained as white solid (0.076 g).

MS (APCI) 481/482 (M+H)⁺

¹H NMR δ (DMSO) 8.80-8.78 (1H, m), 8.63 (1H, t), 8.33 (1H, s), 7.68 (1H,dd), 7.50 (1H, d), 7.52-7.44 (1H, m), 7.28 (1H, d), 7.00 (1H, dd), 4.89(1H, s), 4.52-4.44 (1H, m), 3.83-3.74 (1H, m), 3.44-3.28 (2H, m),2.83-2.66 (2H, m), 2.44-2.23 (4H, m), 2.02-1.90 (2H, m), 1.82-1.72 (2H,m).

EXAMPLE 10N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 1 from(2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1g) and 1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (0.059 g). Titlecompound obtained as white solid (0.047 g).

MS (APCI) 490/492 (M+H)⁺

¹H NMR δ (DMSO) 11.59 (1H, d), 8.33 (1H, t), 8.22 (2H, dd), 7.73 (1H,t), 7.54-7.48 (3H, m), 7.26 (1H, d), 6.98 (1H, dd), 4.79 (1H, s),4.48-4.40 (1H, m), 3.85-3.76 (1H, m), 3.43-3.31 (1H, m), 3.14 (1H,quintet), 2.83-2.69 (2H, m), 2.45-2.25 (4H, m), 1.96-1.87 (2H, m),1.67-1.55 (2H, m).

EXAMPLE 11N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1,3-benzothiazole-6-carboxamide

Prepared as described in Example 1 from(2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1g) and 1,3-benzothiazole-6-carboxylic acid (0.056 g). Title compoundobtained as white solid (0.066 g).

MS (APCI) 480/482 (M+H)⁺

¹H NMR δ (DMSO) 9.54 (1H, s), 8.67 (1H, d), 8.60 (1H, t), 8.15 (1H, d),8.02 (1H, dd), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.78 (1H,brs), 4.47-4.39 (1H, m), 3.87-3.79 (1H, m), 3.44 (1H, dt), 3.23 (1H,quintet), 2.82-2.68 (2H, m), 2.40 (1H, dd), 2.37-2.23 (3H, m), 1.96-1.86(2H, m), 1.66-1.54 (2H, m).

EXAMPLE 123-Cyano-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide

Prepared as described in Example 1 from(2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.2g) and 3-cyanobenzoic acid (0.092 g). Title compound obtained as whitesolid (0.050 g).

MS (APCI) 448/450 (M+H)⁺

¹H NMR δ (CDCl₃) 8.10 (1H, s), 7.79 (1H, d), 7.58 (1H, t), 7.31 (1H, d),7.00 (1H, d), 6.80 (1H, t), 6.75 (1H, dd), 4.38-4.25 (1H, m), 4.00-3.87(1H, m), 3.81-3.68 (1H, m), 3.36 (1H, dt), 2.98-2.85 (1H, m), 2.75-2.63(1H, m), 2.63-2.53 (1H, m), 2.48 (1H, dd), 2.37 (1H, d), 2.32 (2H, t),2.07-1.90 (2H, m), 1.90-1.73 (2H, m).

EXAMPLE 13N-{4-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-3-hydroxybutyl}-2-(methylsulfonyl)benzamide

Prepared as described in Example 1 from4-amino-1-[4-(3,4-dichlorophenoxy)piperidin-1-yl]butan-2-ol (0.26 g) and2-(methylsulphonyl)benzoic acid (0.156 g). The title compound wasobtained as a white solid (0.170 g).

MS (APCI) 515/517 (M+H)⁺

¹H NMR δ (CDCl₃) 8.09 (1H, dd), 7.65 (1H, dd), 7.59 (1H, td), 7.53 (1H,dd), 7.31 (1H, d), 6.99 (1H, d), 6.74 (1H, dd), 6.74 (1H, dd), 4.32-4.23(1H, m), 3.92-3.83 (1H, m), 3.83-3.74 (1 Hz, m), 3.57-3.46 (1H, m), 3.37(3H, s), 2.94-2.85 (1H, m), 2.60-2.50 (1H, m), 2.40 (1H, dd), 2.35 (1H,dd), 2.32-2.23 (1H, m), 2.01-1.89 (2H, m), 1.88-1.69 (2H, m), 1.67-1.55(2H, m).

EXAMPLE 14N-{4-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-3-hydroxybutyl}-2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxamide

Prepared as described in Example 1 from4-amino-1-[4-(3,4-dichlorophenoxy)piperidin-1-yl]butan-2-ol (0.26 g) and2-oxo-2,3-dihydro-1,3-benzothiazole-6-carboxylic acid (0.152 g). Titlecompound obtained as a white solid (0.105 g).

MS (APCI) 510/512 (M+H)⁺

¹H NMR δ (CDCl₃) 7.88 (1H, d), 7.71 (1H, dd), 7.48-7.39 (1H, m), 7.31(1H, d), 7.13 (1H, d), 7.00 (1H, d), 6.76 (1H, dd), 4.36-4.27 (1H, m),3.93-3.83 (2H, m), 3.49-3.38 (1H, m), 2.97-2.87 (1H, m), 2.73-2.53 (2H,m), 2.46-2.32 (2H, m), 2.36-2.27 (1H, m), 2.06-1.91 (2H, m), 1.90-1.75(3H, m), 1.66-1.53 (1H, m).

EXAMPLE 154-Amino-N-{4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-3-hydroxybutyl}-3-methoxybenzamide

Prepared as described in Example 1 from4-amino-1-[4-(3,4-dichlorophenoxy)piperidin-1-yl]butan-2-ol (0.26 g) and4-amino-3-methoxybenzoic acid (0.130 g). Title compound obtained aswhite solid (0.080 g).

MS (APCI) 482/484 (M+H)⁺

¹H NMR δ (CDCl₃) 7.39 (1H, d), 7.31 (1H, d), 7.15 (1H, dd), 7.04 (1H,bs), 7.00 (1H, d), 6.75 (1H, dd), 6.65 (1H, d), 4.29 (1H, septet), 4.08(2H, bs), 3.90 (3H, s), 3.89-3.75 (2H, m), 3.49-3.36 (1H, m), 2.96-2.85(1H, m), 2.73-2.61 (1H, m), 2.61-2.50 (1H, m), 2.44-2.34 (2H, m),2.35-2.23 (1H, m), 2.07-1.90 (2H, m), 1.90-1.71 (2H, m), 1.70-1.48 (2H,m).

EXAMPLE 16N-{4-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxybutyl}-2-(methylsulfonyl)benzamide

Prepared as described in Example 1 from1-amino-4-[4-(3,4-dichlorophenoxy)piperidin-1-yl]butan-2-ol (0.2 g) and2-(methylsulphonyl)benzoic acid (0.12 g). Title compound obtained aswhite solid (0.090 g).

MS (APCI) 515/517 (M+H)⁺

¹H NMR δ (CDCl₃) 8.10 (1H, d), 7.67 (1H, td), 7.61 (1H, td), 7.55 (1H,dd), 7.30 (1H, d), 6.98 (1H, d), 6.73 (1H, dd), 6.61 (1H, t), 4.33-4.23(1H, m), 4.06 (1H, octet), 3.70 (1H, ddd), 3.36-3.29 (1H, m), 3.37 (3H,s), 2.97-2.82 (1H, m), 2.78-2.68 (1H, m), 2.64 (1H, dt), 2.60-2.47 (2H,m), 2.38-2.22 (1H, m), 2.02-1.41 (6H, m).

The compounds of Examples 17 and 18 were prepared in a similar way toExample 1 following Preparation 13 starting from4-(2,4-dichloro-3-methylphenoxy)piperidine (WO 00/58305, WO 01/77101).

EXAMPLE 17N-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 13.

MS (APCI) 504/506 (M+H)⁺

¹H NMR δ (DMSO) 11.58 (1H, s), 8.31 (1H, t), 8.22 (2H, d), 7.72 (1H, t),7.56-7.48 (2H, m), 7.35 (1H, d), 7.10 (1H, d), 4.80-4.70 (1H, m),4.53-4.44 (1H, m), 3.85-3.75 (1H, m), 3.39 (1H, dt), 3.15 (1H, quintet),2.78-2.64 (2H, m), 2.40 (3H, s), 2.39-2.27 (4H, m), 1.96-1.83 (2H, m),1.74-1.61 (2H, m).

EXAMPLE 18N-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(methylsulfonyl)benzamide

Prepared as described in Example 1 following Preparation 13.

MS (APCI) 515/517 (M+H)⁺

¹H NMR δ (CDCl₃) 8.10 (1H, dd), 7.67 (1H, t), 7.62 (1H, t), 7.54 (1H,dd), 7.19 (1H, d), 6.74 (1H, d), 6.55 (1H, t), 4.41-4.27 (1H, m),4.03-3.89 (1H, m), 3.68 (1, ddd), 3.44 (1H, dt), 3.36 (3H, s), 3.00-2.87(1H, m), 2.80-2.66 (1H, m), 2.63-2.51 (2H, m), 2.51-2.42 (1H, m), 2.47(3H, s), 2.42-2.29 (1H, m), 2.03-1.76 (4H, m).

EXAMPLE 19N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(methylsulfonyl)benzamide

Prepared as described in Example 1 following Preparation 14.

MS (APCI) 501/503 (M+H)⁺

¹H NMR δ (CDCl₃) 8.10 (1H, dd), 7.68 (1H, td), 7.62 (1H, td), 7.54 (1H,dd), 7.31 (1H, d), 6.99 (1H, d), 6.75 (1H, dd), 6.53 (1H, t), 4.35-4.22(1H, m), 3.68 (1H, ddd), 3.45 (1H, dt), 3.36 (3H, s), 2.98-2.85 (1H, m),2.80-2.66 (1H, m), 2.65-2.52 (2H, m), 2.46 (1H, dd), 2.41-2.28 (1H, m),2.04-1.88 (2H, m), 1.87-1.67 (2H, m).

EXAMPLE 20N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-[(methylamino)sulfonyl]benzamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 516/518 (M+H)⁺

¹H NMR δ (CDCl₃) 8.25 (1H, s), 7.99 (1H, d), 7.95 (1H, d), 7.55 (1H, t),7.41 (1H, t), 7.31 (1H, d), 7.00 (1H, d), 6.75 (1H, dd), 4.95 (1H, s),4.36-4.25 (1H, m), 4.16-4.05 (1H, m), 3.75 (1H, ddd), 3.31 (1H, ddd),3.02-2.90 (1H, m), 2.74-2.56 (2H, m), 2.68 (3H, s), 2.51 (1H, dd),2.37-2.26 (1H, m), 2.37 (1H, dd), 2.07-1.91 (2H, m), 1.91-1.72 (2H, m).

EXAMPLE 213,5-Bis(acetylamino)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 537/539 M+H)⁺

¹H NMR δ (CDCl₃) 9.00 (2H, s), 7.86 (1H, s), 7.66 (2H, s), 7.50 (1H, s),7.31 (1H, d), 6.99 (1H, d), 6.74 (1H, dd), 4.42-4.27 (1H, m), 4.19-4.03(1H, m), 3.63-3.46 (1H, m), 3.42-3.26 (1H, m), 3.05-2.91 (1H, m),2.91-2.74 (1H, m), 2.75-2.54 (4H, m), 2.17-1.96 (2H, m), 2.11 (6H, s),1.97-1.79 (2H, m).

EXAMPLE 223-(Acetylamino)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 480/482 (M+H)⁺

¹H NMR δ (CDCl₃) 7.88 (1H, s), 7.78 (1H, d), 7.55-7.45 (2H, m), 7.39(1H, t), 7.31 (1H, d), 6.99 (1H, d), 6.82 (1H, t), 6.75 (1H, dd),4.37-4.22 (1H, m), 3.99-3.85 (1H, m), 3.77-3.63 (1H, m), 3.38 (1H,quintet), 2.96-2.83 (1H, m), 2.75-2.63 (1H, m), 2.63-2.51 (1H, m),2.52-2.24 (3H, m), 2.20 (3H, s), 2.08-1.90 (2H, m), 1.90-1.69 (2H, m).

EXAMPLE 23N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1H-pyrazole-4-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 413/415 (M+H)⁺

¹H NMR δ (CDCl₃) 8.02 (2H, s), 7.33 (1H, d), 7.00 (1H, s), 6.95 (1H, t),6.76 (1H, d), 4.44-4.33 (1H, m), 4.07-3.98 (1H, m), 3.74-3.61 (1H, m),3.40 (1H, td), 2.89-2.77 (2H, m), 2.62 (2H, d), 2.68-2.56 (1H, m),2.18-1.99 (2H, m), 1.98-1.82 (2H, m).

EXAMPLE 242-(Acetylamino)-5-bromo-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 558/460/562 (M+H)⁺

¹H NMR δ (CDCl₃) 10.98 (1H, s), 8.52 (1H, d), 7.66 (1H, s), 7.55 (1H,d), 7.32 (1H, d), 7.26 (1H, s), 7.16-7.05 (2H, m), 7.00 (1H, s), 6.76(1H, d), 4.42-4.30 (1H, m), 4.06-3.94 (1H, m), 3.72-3.59 (2H, m),3.43-3.29 (1H, m), 2.95 (1H, t), 2.75 (2H, t), 2.59-2.43 (3H, m), 2.19(3H, s), 2.13-1.96 (5H, m), 1.96-1.78 (3H, m).

EXAMPLE 25N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-oxo-1,2-dihydropyridine-3-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 440/442 (M+H)⁺.

¹H NMR δ (CDCl₃) 9.86 (1H, t), 8.61 (1H, dd), 7.53 (1H, dd), 7.31 (1H,d), 6.99 (1H, d), 6.75 (1H, dd), 6.52 (1H, t), 4.33-4.24 (1H, m),3.97-3.89 (1H, m), 3.70 (1H, ddd), 3.44 (1H, td), 2.94-2.85 (1H, m),2.73-2.63 (1H, m), 2.59-2.50 (1H, m), 2.49-2.37 (2H, m), 2.30 (1H, t),2.04-1.90 (2H, m), 1.87-1.72 (2H, m).

EXAMPLE 26N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-5-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 490/492 (M+H)⁺

¹H NMR δ (DMSO) 11.34 (1H, d), 8.46 (1H, t), 8.28 (1H, d), 7.78 (1H,dd), 7.50 (1H, t), 7.49 (1H, d), 7.25 (1H, d), 7.23-7.16 (1H, m), 6.98(1H, dd), 6.81 (1H, d), 4.72 (1H, d), 4.49-4.37 (1H, m), 3.87-3.76 (1H,m), 3.46-3.35 (1H, m), 3.30-3.16 (1H, m), 2.83-2.67 (2H, m), 2.47-2.23(4H, m), 1.97-1.84 (2H, m), 1.68-1.50 (2H, m).

EXAMPLE 27N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}quinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 474/476 (M+H)⁺

¹H NMR δ (CD₃OD) 1.69-1.79 (m, 2H), 1.90-2.00 (m, 2H), 2.53-2.65 (m, 4H)2.84-2.94 (m, 2H), 3.39 (dd, 1H), 3.54 (dd, 1H), 3.99-4.05 (m, 1H),4.33-4.40 (m, 1H), 6.81 (dd, 1H), 7.03 (d, 1H), 7.29 (d, 1H), 7.52 (d,1H), 7.59 (t, 1H), 7.73 (t, 1H), 8.00 (d, 1H), 8.15 (d, 1H), 8.83 (d,1H).

EXAMPLE 28N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1H-indole-4-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 462/464 (M+H)⁺

¹H NMR δ (CD₃OD) 1.82-1.91 (m, 2H), 2.00-2.13 (m, 2H), 2.63-2.76 (m,4H), 2.96-3.05 (m, 2H), 3.44 (dd, 1H), 3.54 (dd, 1H), 4.04-4.11 (m, 1H),4.43-4.50 (m, 1H), 5.50 (s, 1H), 6.56 (d, 1H), 6.90 (dd, 1H), 7.12 (d,1H), 7.32 (d, 1H), 7.38 (d, 1H), 7.43 (d, 1H), 7.63 (dd, 1H), 8.14 (s,1H).

EXAMPLE 292-(Acetylamino)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 480/482 (M+H)⁺

¹H NMR δ (CDCl₃) 11.05 (1H, bd s), 8.60 (1H, d), 7.52-7.46 (2H, m), 7.31(1H, d), 7.08 (1H, t), 6.99 (1H, d), 6.81 (1H, bd s), 6.76 (1H, dd),4.36-4.28 (1H, m), 3.96-3.90 (1H, m), 3.72-3.64 (1H, m), 3.40-3.32 (1H,m), 2.94-2.86 (2H, m), 2.72-2.58 (2H, m), 2.49-2.31 (3H, m), 2.20 (3H,s), 2.03-1.93 (2H, m), 1.89-1.79 (2H, m).

EXAMPLE 302-(Acetylamino)-5-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 514/516/518 (M+H)⁺

¹H NMR δ (CDCl₃) 10.94 (1H, bd s), 8.59 (1H, d), 7.47 (1H, d), 7.43 (1H,dd), 7.32 (1H, d), 7.00 (1H, d), 6.87 (1H, bd s), 6.76 (1H, dd),4.36-4.28 (1H, m), 3.97-3.90 (1H, m), 3.68-3.61 (1H, m), 3.38-3.32 (1H,m), 2.94-2.88 (1H, m), 2.72-2.58 (2H, m), 2.50-2.33 (3H, m), 2.19 (3H,s), 2.05-1.95 (2H, m), 1.90-1.80 (2H, m).

EXAMPLE 312-(Acetylamino)-4-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 514/516/518 (M+H)⁺

¹H NMR δ (CDCl₃) 11.19 (1H, bd s), 8.73 (1H, d), 7.42 (1H, d), 7.32 (1H,d), 7.05 (1H, d), 7.00 (1H, d), 6.78-6.74 (2H, m), 4.36-4.28 (1H, m),3.96-3.88 (1H, m), 3.70-3.62 (1H, m), 3.38-3.30 (1H, m), 2.94-2.88 (1H,m), 2.70-2.58 (2H, m), 2.49-2.30 (3H, m), 2.20 (3H, s), 2.04-1.96 (2H,m), 1.90-1.78 (2H, m).

EXAMPLE 325-Chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-[(methylsulphonyl)amino]benzamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 550/552/554 (M+H)⁺

¹H NMR δ (CDCl₃) 7.69 (1H, d), 7.52 (1H, s), 7.45 (1H, d), 7.31 (1H, d),7.00 (1H, d), 6.75 (1H, dd), 4.36-4.28 (1H, m), 3.96-3.90 (1H, m),3.72-3.64 (1H, m), 3.36-3.30 (1H, m), 3.04 (3H, s), 2.95-2.89 (1H, m),2.74-2.56 (2H, m), 2.50-2.30 (3H, m), 2.05-1.95 (2H, m), 1.90-1.88 (2H,m).

EXAMPLE 334-Chloro-N-{(2R)-3-(4-(3,4-chlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-[(methylsulphonyl)amino]benzamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 550/552/554 (M+H)⁺

¹H NMR δ (CDCl₃) 7.75 (1H, d), 7.48 (1H, d), 7.31 (1H, d), 7.09 (1H,dd), 7.00 (1H, d), 6.75 (1H, dd), 4.38-4.28 (1H, m), 3.97-3.87 (1H, m),3.72-3.66 (1H, m), 3.34-3.28 (1H, m), 3.08 (3H, s), 2.98-2.90 (1H, m),2.76-2.58 (2H, m), 2.50-2.30 (3H, m), 2.10-1.94 (2H, m), 1.90-1.74 (2H,m).

EXAMPLE 342-Amino-4-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 472/474/476 (M+H)⁺

¹H NMR δ (CDCl₃) 7.31 (1H, d), 7.27 (1H, d), 6.99 (1H, d), 6.75 (1H,dd), 6.67 (1H, d), 6.61 (1H, dd), 6.55 (1H, t), 5.64 (2H, bd s),4.34-4.24 (1H, m), 3.92-3.82 (1H, m), 3.68-3.62 (1H, m), 3.36-3.29 (1H,m), 2.94-2.86 (1H, m), 2.70-2.54 (2H, m), 2.47-2.29 (2H, m), 2.26-2.16(1H, m), 2.04-1.94 (2H, m), 1.88-1.78 (2H, m).

EXAMPLE 355-Chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-6-oxo-1,6-dihydropyridine-3-carboxamide

To a solution of(2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (150mg, 0.47 mmol) and triethylamine (48 mg, 66 μl, 0.47 mmol) indichloromethane (20 ml) was added a solution of5-chloro-6-hydroxynicotinyl chloride (90 mg, 0.47 mmol) indichloromethane (10 ml). The mixture was stirred at room temperature for3 h and then the solution was concentrated in vacuo to leave a crudeoil. Purification by reverse phase HPLC (Symmetry, 0.1% ammoniumacetate/acetonitrile) afforded the title compound as a colourless glass(150 mg, 67%).

MS (APCI) 474/476/478 (M+H)⁺

¹H NMR δ (CDCl₃) 8.07 (1H, d), 8.04 (1H, d), 7.31 (1H, d), 7.09 (1H, bds), 6.99 (1H, d), 6.75 (1H, dd), 4.36-4.26 (1H, m), 4.00-3.90 (1H, m),3.68-3.58 (1H, m), 3.32-3.22 (1H, m), 2.96-2.86 (1H, m), 2.76-2.58 (2H,m), 2.51-2.35 (3H, m), 2.04-1.94 (2H, m), 1.88-1.76 (2H, m).

EXAMPLE 362-(Aminosulphonyl)-4-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 536/538/540 (M+H)⁺

¹H NMR δ (CDCl₃) 8.39 (1H, d), 7.90 (1H, bd s), 7.78 (1H, dd), 7.45 (1H,d), 7.32 (1H, d), 7.00 (1H, d), 6.76 (1H, dd), 4.38-4.22 (2H, m),3.76-3.62 (1H, m), 3.30-3.20 (1H, m), 3.10-3.00 (1H, m), 2.80-2.68 (2H,m), 2.60-2.40 (3H, m), 2.10-2.00 (2H, m), 1.96-1.86 (2H, m).

EXAMPLE 37N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1H-indazole-3-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 463/465 (M+H)⁺

¹H NMR δ (CDCl₃) 8.43-8.33 (2H, m), 7.54 (1H, d), 7.43 (1H, t), 7.32(1H, d), 6.99 (1H, d), 6.75 (1H, dd), 4.38-4.28 (1H, m), 4.15-4.05 (1H,m), 3.75-3.65 (1H, m), 3.60-3.48 (1H, m), 3.02-2.92 (1H, m), 2.80-2.50(4H, m), 2.45-2.37 (1H, m), 2.10-1.95 (2H, m), 1.90-1.75 (2H, m).

EXAMPLE 381-tert-Butyl-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-methyl-1H-pyrazole-5-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 483/485 (M+H)⁺

¹H NMR δ (CDCl₃) 7.31 (1H, d), 6.99 (1H, d), 6.75 (1H, dd), 6.43 (1H, bds), 6.21 (1H, s), 4.35-4.25 (1H, m), 3.92-3.82 (1H, m), 3.70-3.58 (1H,m), 3.38-3.28 (1H, m), 2.95-2.85 (2H, m), 2.70-2.50 (2H, m), 2.45-2.30(3H, m), 2.24 (3H, s), 2.05-1.90 (2H, m), 1.90-1.78 (2H, m), 1.67 (9H,s).

EXAMPLE 39N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 467/469 (M+H)⁺

¹H NMR δ (DMSO) 12.69 (1H, s), 7.83 (1H, bd s), 7.49 (1H, d), 7.25 (1H,d), 6.98 (1H, dd), 4.80 (1H, d), 4.43 (1H, quintet), 3.73 (1H, q),3.39-3.16 (2H, m), 2.80-2.52 (6H, m), 2.38-2.23 (4H, m), 1.96-1.86 (2H,m), 1.78-1.58 (6H, m).

EXAMPLE 40N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 481/483 (M+H)⁺

¹H NMR δ (CDCl₃) 8.11 (1H, s), 7.32 (1H, d), 7.00 (1H, d), 6.75 (1H,dd), 6.70 (1H, bd s), 4.38-4.28 (1H, m), 4.00-3.90 (1H, m), 3.70-3.60(1H, m), 3.42-3.32 (1H, m), 2.98-2.88 (1H, m), 2.75-2.58 (2H, m),2.50-2.36 (3H, m), 2.10-1.96 (2H, m), 1.92-1.76 (2H, m).

EXAMPLE 41N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-methylimidazo[1,2-a]pyridine-3-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 477/479 (M+H)⁺

¹H NMR δ (CDCl₃) 9.40 (1H, d), 7.58 (1H, d), 7.36-7.30 (2H, m), 7.00(1H, d), 6.92 (1H, t), 6.76 (1H, dd), 6.35 (1H, bd s), 4.38-4.28 (1H,m), 4.01-3.93 (1H, m), 3.82-3.72 (1H, m), 3.48-3.40 (1H, m), 2.98-2.90(1H, m), 2.75 (3H, s), 2.70-2.58 (1H, m), 2.54-2.30 (4H, s), 2.06-1.96(2H, m), 1.94-1.76 (2H, m).

EXAMPLE 42N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4-(1H-pyrazol-3-yl)benzamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 489/491 (M+H)⁺

¹H NMR δ (CDCl₃) 7.84 (2H, d), 7.76 (2H, d), 7.64 (1H, d), 7.34-7.29(2H, m), 7.00 (1H, d), 6.75 (1H, dd), 6.66 (1H, d), 4.45-4.35 (1H, m),4.18-4.08 (1H, m), 3.78-3.66 (1H, m), 3.52-3.42 (1H, m), 3.06-2.96 (1H,m), 2.90-2.80 (2H, m), 2.75-2.63 (3H, m), 2.18-2.03 (2H, m), 2.00-1.80(2H, m).

EXAMPLE 43N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}cinnoline-4-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 475/477 (M+H)⁺

¹H NMR δ (CDCl₃) 9.41 (1H, s), 8.61 (1H, d), 8.38 (1H, d), 7.94-7.82(2H, m), 7.33 (1H, d), 7.20 (1H, bd s), 7.01 (1H, d), 6.76 (1H, dd),4.46-4.36 (1H, m), 4.18-4.08 (1H, m), 3.88-3.78 (1H, m), 3.56-3.46 (1H,m), 3.06-2.96 (1H, m), 2.94-2.78 (2H, m), 2.70-2.60 (3H, m), 2.03-1.89(4H, m).

EXAMPLE 44N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-oxo-1,2-dihydroquinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 490/492 (M+H)⁺

¹H NMR δ (DMSO) 8.69 (1H, t), 7.74 (1H, d), 7.53 (1H, t), 7.49 (1H, d),7.34 (1H, d), 7.25 (1H, d), 7.18 (1H, t), 6.98 (1H, dd), 6.54 (1H, s),4.50-4.40 (1H, m), 3.87-3.77 (1H, m), 3.48-3.40 (1H, m), 3.28-3.18 (1H,m), 2.82-2.70 (2H, m), 2.44-2.24 (4H, m), 1.97-1.87 (2H, m), 1.68-1.56(2H, m).

EXAMPLE 45N-{3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

Prepared as described in Example 35, using2-oxo-2,3-dihydro-1H-benzimidazole-1-carbonyl chloride.

MS (APCI) 479/481 (M+1)⁺

¹H NMR δ (CDCl₃) 9.02 (1H, t), 8.17-8.14 (1H, d), 7.32 (1H, d),7.18-7.12 (2H, m), 7.08-7.05 (1H, m), 7.00 (1H, d), 6.75 (1H, dd),4.42-4.32 (1H, m), 4.16-4.06 (1H, m), 3.71-3.61 (1H, m), 3.49-3.39 (1H,m), 3.04-2.94 (1H, m), 2.85-2.75 (2H, m), 2.71-2.57 (3H, m), 2.16-1.98(2H, m), 1.96-1.80 (2H, m).

EXAMPLE 46N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-oxo-3,4-dihydrophthalazine-1-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 491/493/495 (M+H)⁺

¹H NMR δ (CDCl₃) 9.13 (1H, d), 8.43 (1H, d), 7.91-75 (3H, m), 7.32 (1H,d), 7.00 (1H, d), 6.76 (1H, dd), 4.40-4.32 (1H, m), 4.08-3.98 (1H, m),3.76-3.66 (1H, m), 3.46-3.38 (1H, m), 3.00-2.92 (1H, m), 2.80-2.66 (2H,m), 2.58-2.44 (3H, m), 2.14-1.98 (2H, m), 1.96-1.80 (2H, m).

EXAMPLE 47N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1H-indole-3-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 462/464/466 (M+M)⁺

¹H NMR δ (CDCl₃) 9.03 (1H, bd s), 8.07-8.04 (1H, d), 7.84 (1H, s),7.45-7.41 (1H, m), 7.32 (1H, d), 7.28-7.22 (2H, m), 6.99 (1H, d), 6.82(1H, t), 6.74 (1H, dd), 4.44-4.34 (1H, m), 4.16-4.06 (1H, m), 3.78-3.68(1H, m), 3.56-3.44 (1H, m), 3.04-2.94 (1H, m), 2.92-2.82 (2H, m),2.77-2.65 (3H, m), 2.18-1.98 (2H, m), 1.98-1.78 (2H, m).

EXAMPLE 48N-{(2R)-3-[4-(4-Chlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(methylsulfonyl)benzamide

Prepared as described in Example 1 following Preparation 4.

MS (APCI) 467/469 (M+H)⁺

¹H NMR δ (CD₃OD) 8.08 (1H, d), 7.79 (1H, t), 7.71 (1H, t), 7.61 (1H, d),7.26 (2H, d), 6.95 (2H, d), 4.56-4.45 (1H, m), 4.21-4.08 (1H, m), 3.47(2H, d), 3.35 (3H, s), 3.22-3.08 (2H, m), 3.01-2.77 (4H, m), 2.18-2.00(2H, m), 1.99-1.83 (2H, m).

EXAMPLE 49N-{(2-R)-3-[4-(4-Chlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 4.

MS (APCI) 466/468 (M+H)⁺

¹H NMR δ (DMSO) 11.57 (1H, d), 8.30 (1H, t), 8.22 (2H, d), 7.73 (1H, t),7.58-7.45 (2H, m), 7.30 (2H, d), 6.97 (2H, d), 4.75 (1H, s), 4.41-4.29(1H, m), 3.87-3.74 (1H, m), 3.46-3.26 (1H, m), 3.22-3.07 (1H, m),2.85-2.67 (2H, m), 2.41-2.21 (4H, m), 2.00-1.84 (2H, m), 1.70-1.51 (2H,m).

EXAMPLE 50N-{(2R)-3-[4-(4-Chloro-3-fluorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo1,2-dihydroisoquoline-4-carboxamide

Prepared as described in Example 1 following Preparation 5.

MS (APCI) 474/476 (M+H)⁺

¹H NMR δ (CD₃OD) 8.25 (1H, d), 8.08 (1H, d), 7.67 (1H, ddd), 7.48 (2H,t), 7.21 (1H, t), 6.75 (1H, d), 6.66 (1H, ddd), 4.30 (1H, dq), 3.95-3.87(1H, m), 3.45 (1H, dd), 3.29-3.24 (1H, m), 2.80-2.69 (2H, m), 2.45-2.31(4H, m), 1.95-1.86 (2H, m), 1.73-1.62 (2H, m).

EXAMPLE 51N-{(2R)-3-[4-(3,4-Difluorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 6.

MS (APCI) 458 (M+H)⁺

¹H NMR δ (CD₃OD) 8.25 (1H, dd), 8.08 (1H, d), 7.67 (1H, ddd), 7.50-7.46(2H, m), 7.03 (1H, dt), 6.76 (1H, ddd), 6.63-6.59 (1H, m), 4.24 (1H,dquintet), 3.94-3.87 (1H, m), 3.45 (1H, dd), 3.26 (1H, dd), 2.74 (2H,d), 2.45-2.30 (4H, m), 1.90 (2H, dt), 1.72-1.61 (2H, m).

EXAMPLE 52N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-N-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 12.

MS (APCI) 504/506 (M+H)⁺

¹H NMR δ (DMSO) 1.25-1.42 (m, 1H), 1.57-1.73 (m, 2H), 1.89-2.15 (m, 3H),2.26-2.42 (m, 2H), 2.69-2.85 (m, 1H), 2.90-3.15 (m, 4H), 3.63-3.77 (m,1H), 3.97-4.09 (m, 1H), 4.26-4.49 (m, 1H), 4.79-4.95 (m, 1H), 6.91-7.01(m, 1H), 7.18-7.31 (m, 2H), 7.45-7.57 (m, 3H), 7.73 (t, 1H), 8.23 (d,1H), 11.51 (s, 1H).

EXAMPLE 53N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-N-methyl-1H-indazole-3-carboxamide

Prepared as described in Example 1 following Preparation 12.

MS (APCI) 477/479 (M+H)⁺

¹H NMR δ (DMSO) 1.36-1.51 (m, 1H), 1.58-1.67 (m, 1H), 1.72-1.81 (m, 1H),1.86-1.96 (m, 1H), 2.04-2.21 (m, 2H), 2.26-2.39 (m, 2H), 2.71-2.81 (m,1H), 3.13 (s, 3H), 3.49-3.57 (m, 1H), 3.78-3.93 (m, 1H), 3.98-4.06 (m,1H), 4.31-4.48 (m, 1H), 4.71-4.83 (m, 1H), 6.93-7.00 (m, 1H), 7.16-7.25(m, 2H), 7.34-7.43 (m, 1H), 7.49 (d, 1H), 7.58 (t, 1H), 7.95 (dd, 1H),13.34-13.49 (m, 1H).

EXAMPLE 54N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-N-methyl-4-oxo-3,4-dihydrophthalazine-1-carboxamide

Prepared as described in Example 1 following Preparation 12.

MS (APCI) 505/507 (M+H)⁺

¹H NMR δ (CD₃OD) 1.44-1.55 (m, 1H), 1.69-1.80 (m, 2H), 1.93-2.02 (m,1H), 2.15-2.24 (m, 1H), 2.19 (d, 1H), 2.46-2.60 (m, 2H), 2.84-2.93 (m,1H), 3.20 (s, 3H), 3.42-3.51 (m, 1H), 3.75 (dd, 1H), 3.84 (qt, 1H),4.16-4.25 (m, 1H), 4.35-4.41 (m, (ddd, 1H), 7.00 (dd, 1H), 7.28 (dd,1H), 7.72-7.89 (m, 3H), 8.31 (t, 1H).

EXAMPLE 55 Benzoic acid,3-[[2-[[(2R)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl]amino]-2-oxoethyl]amino]-,methyl ester

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 510/512 (M+H)⁺

¹H NMR δ (CDCl₃) 8.17 (1H, t), 7.95 (1H, dd), 7.38 (1H, t), 7.31 (1H,d), 6.98 (1H, d), 6.91 (1H, t), 6.78-6.68 (2H, m), 6.57 (1H, d),4.32-4.20 (1H, m), 3.92 (2H, d), 3.89 (3H, s), 3.80-3.69 (1H, m),3.52-3.40 (1H, m), 3.26 (1H, dt), 2.87-2.74 (1H, m), 2.62-2.39 (2H, m),2.32 (1H, dd), 2.28-2.14 (2H, m), 2.00-1.84 (−2H, m), 1.83-1.66 (2H, m).

EXAMPLE 56 Propanamide,N-[2-[[2-[[(2R)-3-[3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl]amino]-2-oxoethyl]amino]phenyl]-

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 523/525 (M+H)⁺

¹H NMR δ (CDCl₃) 7.48 (1H, t), 7.31 (1H, d), 7.23-7.11 (2H, m), 7.05(1H, d), 6.98 (2H, d), 6.83-6.71 (2H, m), 6.67 (1H, d), 4.54 (1H, t),4.31-4.17 (1H, m), 3.92 (1H, d), 3.79-3.66 (1H, m), 3.45 (1H, td), 3.22(1H, td), 2.78-2.66 (1H, m), 2.61-2.43 (1H, m), 2.49 (2H, q), 2.37 (1H,t), 2.26-2.06 (3H, m), 1.98-1.82 (2H, m), 1.82-1.64 (2H, m), 1.29 (3H,t).

EXAMPLE 57 Propanamide,N-[2-[[2-[[(2R)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl]amino]-2-oxoethyl]amino]phenyl]-

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 494/496 (M+H)⁺

¹H NMR δ (CDCl₃) 7.73 (2H, dd), 7.32 (UH, dd), 7.29-7.21 (2H, m),7.02-6.97 (1H, m), 6.97-6.88 (1H, m), 6.80-6.71 (1H, m), 6.60-6.49 (1H,m), 4.36-4.23 (1H, m), 4.14 (2H, t), 3.89-3.75 (1H, m), 3.62-3.48 (1H,m), 3.31-3.17 (1H, m), 2.94-2.81 (1H, m), 2.72-2.59 (1H, m), 2.60-2.47(1H, m), 2.43-2.22 (3H, m), 2.40 (3H, s), 2.05-1.89 (2H, m), 1.88-1.72(2H, m).

EXAMPLE 58(2S)-N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-hyroxy-2-phenylethanamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 453/455/457 (M+H)⁺

¹H NMR δ (CDCl₃) 7.44-7.26 (6H, m), 6.98 (1H, d), 6.74 (1H, dd), 6.54(1H, bd s), 5.06 (1H, s), 4.34-4.24 (1H, m), 3.83-3.73 (1H, m),3.56-3.43 (1H, m), 3.32-3.20 (1H, m), 2.88-2.80 (1H, m), 2.62-2.52 (2H,m), 2.33-2.10 (3H, m), 2.02-1.90 (2H, m), 1.86-1.70 (2H, m).

EXAMPLE 592-[2-({(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}amino)-2-oxoethoxy]benzamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 496/498 (M+H)⁺

¹H NMR δ (CDCl₃) 7.97 (1H, d), 7.48 (1H, t), 7.36-7.28 (2H, m),7.17-7.07 (1H, m), 7.13 (2H, t), 6.99 (1H, s), 6.93 (1H, d), 6.75 (1H,d), 5.99 (1H, s), 4.68 (2H, s), 4.35-4.22 (1H, m), 3.89-3.77 (1H, m),3.67-3.54 (1H, m), 3.22 (1H, quintet), 2.91-2.79 (1H, m), 2.68-2.46 (2H,m), 2.43-2.20 (3H, in), 2.04-1.88 (2H, m), 1.88-1.71 (2H, m).

EXAMPLE 60N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 508/510 (M+H)⁺

¹H NMR δ (CDCl₃) 7.31 (1H, d), 7.08-7.01 (4H, m), 6.99 (1H, d), 6.74(1H, dd), 6.53 (1H, bd s), 4.69 (2H, s), 4.56-2H, q), 4.34-4.24 (1H, m),3.80-3.72 (1H, m), 3.52-3.42 (1H, m), 3.28-3.18 (1H, m), 2.88-2.80 (1H,m), 2.63-2.45 (4H, m), 2.36-2.21 (3H, m), 2.00-1.90 (2H, m), 1.86-1.70(2H, m).

Further Examples of compounds of the invention which have been preparedas described in Example 1 following Preparation 7 are presented in theTable below.

Example Name (M + H)⁺ 61N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4522-methoxybenzamide 62N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4512-(methylamino)benzamide 63N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 423hydroxypropyl)}nicotinamide 64N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 423hydroxypropyl}isonicotinamide 65N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4653-(dimethylamino)benzamide 66N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 5052-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetamide 67N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4396-hydroxynicotinamide 68N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4752-(1H-indol-3-yl)acetamide 69N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 448hydroxypropyl}bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide 70N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4924,7-dimethylpyrazolo[5,1-c][1,2,4]triazine-3-carboxamide 71N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 424hydroxypropyl}pyrazine-2-carboxamide 72N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4649H-purine-6-carboxamide 73N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 473hydroxypropyl}quinoline-6-carboxamide 74N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4912,7-dimethylpyrazolo[1,5-a]pyrimidine-6-carboxamide 75N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4702-(pyrimidin-2-ylthio)acetamide 76N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4795-fluoro-1H-indole-2-carboxamide 77N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4791,3-benzothiazole-6-carboxamide 78N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4895-phenyl-1,3-oxazole-4-carboxamide 79N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4396-hydroxypyridine-2-carboxamide 80N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4933-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxamide 81N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4393-hydroxypyridine-2-carboxamide 82N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4621H-benzimidazole-5-carboxamide 83N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4611H-indole-5-carboxamide 84N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4751-methyl-1H-indole-2-carboxamide 85N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4121H-imidazole-4-carboxamide 86N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4611H-indole-6-carboxamide 87N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4751-methyl-1H-indole-3-carboxamide 88N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4611H-indole-7-carboxamide 89N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 5153-[(methylamino)sulfonyl]benzamide 90N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 5783,4-bis(methylsulfonyl)benzamide 91N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4372-pyridin-3-ylacetamide 92N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4775-hydroxy-1H-indole-2-carboxamide 93N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4401,5-dimethyl-1H-pyrazole-3-carboxamide 94N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 5395-(methylsulfonyl)-1H-indole-2-carboxamide 95N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 474hydroxypropyl}quinoxaline-6-carboxamide 96N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4741,8-naphthyridine-2-carboxamide 97N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 518hydroxypropyl}imidazo[2,1-b][1,3]benzothiazole-2-carboxamide 98N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4902,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide 99N-{(2R)-3-[4-{3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4783-oxo-2,3-dihydro-1H-indazole-4-carboxamide 100N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4783-oxo-2,3-dihydro-1H-indazole-6-carboxamide 101N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4803-(trifluoromethyl)-1H-pyrazole-4-carboxamide 1022-(1H-benzimidazol-1-yl)-N-{(2R)-3-[4-(3,4- 476dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}acetamide 103N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4541-ethyl-3-methyl-1H-pyrazole-5-carboxamide 104N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4265-methyl-1H-pyrazole-3-carboxamide 105N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4284-methyl-1,2,5-oxadiazole-3-carboxamide 1066-chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 496hydroxypropyl}imidazo[1,2-a]pyridine-2-carboxamide 107N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4762-methylimidazo[1,2-a]pyridine-3-carboxamide 108N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 463hydroxypropyl}imidazo[1,2-a]pyrimidine-2-carboxamide 109N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4842-[(4-methylpyrimidin-2-yl)thio]acetamide 110N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4894-oxo-1,4-dihydroquinoline-2-carboxamide 111N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 473hydroxypropyl}quinoline-8-carboxamide 112N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4765-methylimidazo[1,2-a]pyridine-2-carboxamide 113N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 462hydroxypropyl}imidazo[1,2-a]pyridine-2-caxboxamide 114N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4741,6-naphthyridine-2-carboxamide 115N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}- 4802,1,3-benzoxadiazole-5-carboxamide 1-oxide

EXAMPLE 116N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-oxo-1,6-dihydropyridine-3-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 440/442 (M+H)⁺

¹H NMR δ (CD₃OD) 8.07 (1H, d), 7.99 (1H, dd), 7.39 (1H, d), 7.15 (1H,d), 6.92 (1H, dd), 6.53 (1H, d), 4.52 (1H, septet), 4.09-4.01 (1H, m),3.49 (1H, dd), 3.34 (1H, d), 3.11-3.02 (2H, m), 2.86-2.67 (4H, m),2.14-2.03 (2H, m), 1.95 (3H, s), 1.97-1.84 (2H, m).

EXAMPLE 1174-Chloro-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1H-pyrazole-3-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 447/449 (M+H)⁺

¹H NMR δ (CD₃OD) 7.77 (1H, s), 7.37 (1H, d), 7.09 (1H, d), 6.88 (1H,dd), 4.39 (1H, t), 3.95 (1H, quintet), 3.49 (1H, dd), 3.40 (1H, dd),2.86-2.77 (2H, m), 2.52-2.39 (2H, m), 2.49 (2H, d), 2.06-1.96 (2H, m),1.85-1.74 (2H, m).

EXAMPLE 118N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-5-phenyl-1,3-oxazole-4-carboxamide

Prepared as described in Example 35 following Preparation 7 from5-phenyl-1,3-oxazole-4-carbonyl chloride.

MS (APCI) 490/492 (M+H)⁺

¹H NMR δ (CD₃OD) 8.12 (1H, s), 8.10-8.08 (2H, m), 7.40-7.35 (3H, m),7.29 (1H, d), 7.04 (1H, d), 6.81 (1H, dd), 4.39 (1H, septet), 3.95 (1H,quintet), 3.44-3.33 (2H, m), 2.96-2.87 (2H, m), 2.67-2.55 (4H, m),2.03-1.93 (2H, m), 1.85 (3H, s), 1.85-1.75 (2H, m).

EXAMPLE 119N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3,5-dimethyl-1H-pyrazole-4-carboxamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 441/443 (M+H)⁺

¹H NMR δ (CD₃OD) 7.28 (1H, d), 7.00 (1H, d), 6.79 (1H, dd), 4.34-4.26(1H, m), 3.86 (1H, quintet), 3.41 (1H, dd), 3.21 (1H, dd), 2.78-2.67(2H, m), 2.41-2.30 (4H, m), 2.29 (6H, s), 1.95-1.86 (2H, m), 1.73-1.63(2H, m).

EXAMPLE 120(2R)-2-(Acetylamino)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-phenylethanamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 494/496 (M+H)⁺

¹H NMR δ (CD₃OD) 7.34 (2H, d), 7.29-7.18 (4H, m), 6.99 (1H, t), 6.78(1H, dd), 5.29 (1H, s), 4.27 (1H, septet), 3.76-3.65 (1H, m), 3.26-3.08(2H, m), 2.65-2.49 (2H, m), 2.30-2.15 (4H, m), 1.91 (3H, s), 1.90-1.81(2H, m), 1.69-1.58 (2H, m).

EXAMPLE 121 N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1yl]-2-hydroxypropyl}-2-(2-hydroxyphenyl)acetamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 453/455 (M+)⁺

¹H NMR δ (CD₃OD) 7.28 (1H, d), 7.05-6.97 (3H, m), 6.78 (1H, dd),6.72-6.67 (2H, m), 4.27 (1H, dq), 3.72 (1H, quintet), 3.43 (2H, dd),3.21-3.08 (2H, m), 2.68-2.57 (2H, m), 2.32-2.20 (4H, m), 1.90-1.81 (2H,m), 1.69-1.58 (−2H, m).

EXAMPLE 122(2R)-N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-2-phenylethanamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 530/532 (M+H)⁺

¹H NMR δ (CD₃OD) 7.37 (2H, d), 7.31-7.21 (4H, m), 6.99 (1H, d), 6.78(1H, dd), 4.96 (1H, s), 4.27 (1H, septet), 3.70 (1H, quintet), 3.24 (1H,dd), 3.13 (1H, dd), 2.72 (3H, s), 2.66-2.56 (2H, m), 2.32-2.18 (4H, m),1.91-1.82 (2H, m), 1.70-1.59 (2H, m).

EXAMPLE 123(2S)-2-(Acetylamino)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-phenylethanamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 494/496 (M+H)⁺

¹H NMR δ (CD₃OD) 7.34 (2H, d), 7.30-7.18 (4H, m), 6.99 (1H, dd), 6.78(1H, ddd), 5.29 (1H, s), 4.30-4.23 (1H, m), 3.76-3.65 (1H, m), 3.17-3.07(2H, m), 2.65-2.48 (2H, m), 2.30-2.14 (4H, m), 1.92-1.80 (2H, m), 1.91(3H, s), 1.68-1.57 (2H, m).

EXAMPLE 124(2S)-N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-2-phenylethanamide

Prepared as described in Example 1 following Preparation 7.

MS (APCI) 530/5322 (M+H)⁺

¹H NMR δ (CD₃OD) 7.47 (2H, d), 7.40-7.30 (4H, m), 7.08 (1H, d), 6.87(1H, dd), 5.06 (1H, s), 4.39-4.32 (1H, m), 3.83 (1H, quintet), 3.27 (2H,d), 2.80 (3H, s), 2.73-2.59 (2H, m), 2.38-2.24 (2H, m), 2.28 (2H, d),1.99-1.89 (2H, m), 1.78-1.67 (2H, m).

EXAMPLE 1251-{(R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-o-tolyl-urea

A solution of o-tolylisocyanate (64 ml, 0.51 mmol) in dichloromethane (1ml) was added to a suspension of(2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.15g, 0.47 mmol) in dichloromethane (3 ml) over a five minute period. After1 h methanol (1 ml) was added and the solvents removed under vacuum. Theresidue was purified by reverse phase chromatography (C8 Symmetrycolumn) to give the title compound (87 mg).

MS (APCI) 452/454 (M+H)⁺

¹H NMR δ (DMSO) 7.81 (1H, d), 7.78 (1H, s), 7.50 (1H, dd), 7.26 (1H,dd), 7.10 (1H, t), 7.05 (1H, s), 6.99 (1H, ddd), 6.86 (1H, t), 6.63 (1H,t), 4.74 (1H, d), 4.49-4.40 (1H, m), 3.72-3.63 (1H, m), 3.32-3.30 (1H,m), 2.99-2.90 (1H, m), 2.79-2.67 (2H, m), 2.35-2.24 (4H, m), 2.18 (3H,s), 1.97-1.88 (2H, m), 1.69-1.56 (2H, m).

EXAMPLE 1261-{(R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-p-tolyl-urea

Prepared as described in Example 125 following Preparation 1.

MS (APCI) 452/454 (M+H)⁺

¹H NMR δ (DMSO) 8.52 (1H, s), 7.55 (1H, d), 7.31 (2H, d), 7.31 (1H, s),7.07 (2H, d), 7.03 (1H, d), 6.15 (1H, t), 4.82-4.76 (1H, m), 4.55-4.45(1H, m), 3.76-3.67 (1H, m), 3.36-3.32 (1H, m), 3.03-2.95 (1H, m),2.83-2.72 (2H, m), 2.40-2.31 (4H, m), 2.27 (3H, s), 2.03-1.92 (2H, m),1.75-1.61 (2H, m).

EXAMPLE 127N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxy-2-methylpropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 9.

MS (APCI) 504/506/508 (M+H)⁺

¹H NMR δ (CD₃OD) 8.37 (1H, d), 8.18 (1H, d), 7.78 (1H, t), 7.59 (1H, s),7.58 (1H, t), 7.37 (1H, d), 7.07 (1H, d), 6.86 (1H (dd), 4.33-4.28 (1H,m), 3.60-3.45 (2H, m), 3.04-2.92 (2H, m), 2.60-2.45 (4H, m), 1.98-1.86(2H, m), 1.72-1.60 (2H, m), 1.25 (3H, s).

EXAMPLE 128N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxy-2-methylpropyl}-2-oxo-1,2-dihydroquinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 9.

MS (APCI) 504/506/508 (M+H)⁺

¹H NMR δ (CDCl₃) 7.93 (1H, d), 7.53 (1H, t), 7.34-7.20 (4H, m), 6.98(1H, d), 6.75-6.69 (2H, m), 4.32-4.22 (1H, m), 3.68-3.40 (2H, m),3.00-2.80 (2H, m), 2.70-2.48 (4H, m), 2.00-1.86 (2H, m), 1.84-1.72 (2H,m), 1.26 (3H, s).

EXAMPLE 129N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxy-2-methylpropyl}-4-oxo-3,4-dihydrophthalazine-1-carboxamide

Prepared as described in Example 1 following Preparation 9.

MS (APCI) 505/507/509 (M+H)⁺

¹H NMR δ (CDCl₃) 10.18 (1H, bs), 9.15 (1H, d), 8.44 (1H, d), 8.06 (1H,bd s), 7.89 (1H, t), 7.81 (1H, t), 7.31 (1H, d), 7.01 (1H, d), 6.78 (1H,dd), 4.35-4.25 (1H, m), 3.58-3.37 (2H, m), 3.04-2.82 (2H, m), 2.66-2.46(4H, m), 2.06-1.96 (2H, m), 1.94-1.80 (2H, m), 1.23 (3H, s).

EXAMPLE 130(2S)-N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxy-2-methylpropyl}-2-hydroxy-2-phenethanamide

Prepared as described in Example 1 following Preparation 9.

MS (APCI) 467/469/471 (M+H)⁺

¹H NMR δ (CDCl₃) 7.46-7.29 (6H, m), 6.98 (1H, d), 6.78 (1H, bd s), 6.75(1H, dd), 5.08 (1H, s), 4.28-4.20 (1H, m), 3.71 (1H, bd s), 3.35-3.20(2H, m), 2.86-2.69 (2H, m), 2.53-2.39 (2H, m), 2.31 (2H, s), 1.97-1.85(2H, m), 1.82-1.70 (2H, m), 1.04 (3H, s).

EXAMPLE 131N-{(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 10.

MS (APCI) 470/472 (M+H)⁺

¹H NMR δ (CD₃OD) 8.25 (1H, d), 8.08 (1H, d), 7.67 (1H, t), 7.48 (2H, t),7.05-6.96 (2H, m), 6.77 (1H, d), 4.36-4.25 (1H, m), 3.98-3.87 (1H, m),3.45 (1H, dd), 3.28 (1H, dd), 2.80-2.67 (2H, m), 2.49-2.34 (4H, m), 2.08(3H, s), 1.98-1.84 (2H, m), 1.78-1.64 (2H, m).

EXAMPLE 132N-((2R)-3-{4-[2-Aminocarbonyl)-3,4-dichlorophenoxy]piperidin-1-yl}-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

The crude amine product obtained from Preparation 11 was redissolved indichloromethane and treated with diisopropylethylamine 0.85 ml) and1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride (0.40 g) at roomtemperature. The reaction was quenched with saturated aqueous sodiumhydrogen carbonate solution and the mixture concentrated in vacuo,azeotoping with toluene. Extraction of the solid residue intodichloromethane/methanol, filtering solids and chromatography on silica(dichloromethane:7N ammonia in methanol/15:2) gave the target compoundas a white solid (0.31 g).

MS (APCI) 533/535 (M+H)⁺

¹H NMR δ (CD₃OD) 8.25 (1H, d), 8.12 (1H, d), 7.69 (1H, m), 7.55 (1H, s),7.49 (1H, m), 7.44 (1H, d), 7.05 (1H, d), 4.20 (1H, m), 3.55-2.96 (10H,m), 2.25-1.98 (4H, m).

EXAMPLE 1333-Cyano-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}benzenesulfonamide

To a solution of(2-R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol(0.200 g, 0.63 mmol) in 4 ml of pyridine at 0° C. was added3-cyanobenzenesulfonyl chloride (0.127 g, 0.63 mmol). After 30 min, thereaction was allowed to warm to room temperature and was stirred for 2h. The reaction was concentrated under vacuum, and the residuepartitioned between 10% aqueous sodium hydrogen carbonate and ethylacetate. The organic layer was washed with water, then brine and driedover magnesium sulfate. The crude material was purified on silica gel (0to 5% 7N ammonia in methanol/dichloromethane) to afford the titlecompound as a white foam (0.120 g).

MS (ESI) 484/486 (M+H)⁺

¹H NMR δ (DMSO) 8.22 (1H, d), 8.16-8.07 (2H, d), 7.82 (2H, t), 7.50 (1H,d), 7.25 (1H, d), 6.97 (1H, dd), 4.71 (d, 1H), 4.47-4.34 (1H, m),3.63-3.51 (1H, m), 2.93 (1H, dd), 2.71 (1H, dd), 2.69-2.55 (2H, m),2.32-2.12 (4H, m), 1.95-1.79 (2H, m), 1.65-1.45 (2H, m), 1.65-1.45 (2H,m).

EXAMPLE 1345-[({(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}amino)-sulfonyl]-2-methoxybenzamide

Prepared as described in Example 133 following Preparation 7 using3-(aminocarbonyl) 4-methoxybenzenesulfonyl chloride.

MS (APCI) 531/533 (M+H)⁺

¹H NMR δ (DMSO) 8.20 (1H, d), 7.87 (1H, dd), 7.73 (2H, s), 7.55 (1H, s),7.49 (1H, d), 7.32 (1H, d), 7.25 (1H, d), 6.97 (1H, dd), 4.67 (1H, d),4.41 (1H, septet), 3.96 (3H, s), 3.58 (1H, q), 2.82 (1H, d), 2.68-2.57(3H, m), 2.30-2.16 (4H, m), 1.91-1.82 (2H, m), 1.60-1.49 (2H, m).

EXAMPLE 135N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-sulfonamideacetate salt

(2R)-1-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1g) in pyridine (2 ml) was treated with1-oxo-1,2-dihydroisoquinoline-4-sulfonyl chloride (0.11 g) and themixture was stirred at ambient temperature for 18 h. After furtheradditions of the sulfonyl chloride (0.05 g) and stirring for 24 h thesolvent was evaporated. Purification by column chromatography andreverse phase HPLC (symmetry C8 column and acetonitrile/0.1% aqueousammonium acetate) yielded the title compound as a white solid (0.06 g).

MS (APCI) 526/528 (M+H)⁺

¹H NMR δ (DMSO) 8.39 (1H, d), 8.32 (1H, d), 7.95 (1H, s), 7.86 (1H,ddd), 7.64 (1H, t), 7.39 (1H, d), 7.11 (1H, d), 6.89 (1H, dd), 4.45-4.39(1H, m), 3.82-3.75 (1H, m), 3.34 (1H, s), 2.97 (1H, dd), 2.92 (1H, dd),2.81-2.72 (2H, m), 2.55-2.42 (2H, m), 2.02-1.92 (2H, m), 1.95 (3H, s,OAc), 1.82-1.72 (2H, m).

EXAMPLE 136N-{(2S)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2,4-difluorobenzenesulfonamide

Prepared as described in Example 133 following Preparation 7 using2,4-difluorobenzenesulfonyl chloride.

MS (APCI) 493/495 (M+H)⁺

¹H NMR δ (DMSO) 7.94 (1H, s), 7.86 (1H, td), 7.55 (1H, ddd), 7.49 (1H,d), 7.28 (1H, ddd), 7.25 (1H, d), 6.97 (1H, dd), 4.69 (1H, d), 4.42 (1H,septet), 3.60 (1H, sextet), 2.96 (1H, dd), 2.81 (1H, dd), 2.68-2.58 (2H,m), 2.34-2.16 (4H, m), 1.91-1.82 (2H, m), 1.60-1.49 (2H, m).

Further Examples of compounds of the invention which have been preparedaccording to Example 133 following Preparation 7 are now listed in thefollowing table.

Example Name (M + H)⁺ 137N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 396hydroxypropyl}methanesulfonamide 138N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 458hydroxypropyl}benzenesulfonamide 139N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 472hydroxypropyl}-1-phenylmethanesulfonamide 140N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 488hydroxypropyl}-4-methoxybenzenesulfonamide 141N-({5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 597hydroxypropyl}amino)sulfonyl]-2-thienyl}methyl)benzamide 1424-cyano-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 483hydroxypropyl}benzenesulfonamide 143N-{5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 536hydroxypropyl}amino)sulfonyl]-4-methyl-1,3-thiazol-2- yl}acetamide 144N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 464hydroxypropyl}thiophene-2-sulfonamide 1454-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 502hydroxypropyl}amino)sulfonyl]benzoic acid 146N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 518hydroxypropyl}-2,5-dimethoxybenzenesulfonamide 147N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 604hydroxypropyl}-4-(phenylsulfonyl)thiophene-2-sulfonamide 148N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 531hydroxypropyl}-5-(1,3-oxazol-5-yl)thiophene-2-sulfonamide 149N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 612hydroxypropyl}-5-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]thiophene-2-sulfonamide 150N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 541hydroxypropyl}-5-(pyridin-2-yl)thiophene-2-sulfonamide 1515-chloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 510hydroxypropyl}-1,3-dimethyl-1H-pyrazole-4-sulfonamide 152N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 477hydroxypropyl}-3,5-dimethylisoxazole-4-sulfonamide 153N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 516hydroxypropyl}-2,1,3-benzothiadiazole-4-sulfonamide 154N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 462hydroxypropyl}-1-methyl-1H-imidazole-4-sulfonamide 155N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 500hydroxypropyl}-2,1,3-benzoxadiazole-4-sulfonamide 156N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 531hydroxypropyl}-5-(isoxazol-3-yl)thiophene-2-sulfonamide 157 methyl3-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 522hydroxypropyl}amino)sulfonyl]thiophene-2-carboxylate 1582,6-dichloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]- 5262-hydroxypropyl}benzenesulfonamide 159N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 472hydroxypropyl}-3-methylbenzenesulfonamide 1603-chloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 492hydroxypropyl}benzenesulfonamide 161N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 424hydroxypropyl}propane-2-sulfonamide 162N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 424hydroxypropyl}propane-1-sulfonamide 163N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 538hydroxypropyl}-5-methyl-1-phenyl-1H-pyrazole-4-sulfonamide 1643-chloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 506hydroxypropyl}-2-methylbenzenesulfonamide 165 methyl5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 520hydroxypropyl}amino)sulfonyl]-2-methyl-3-furoate 166 methyl5-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 519hydroxypropyl}amino)sulfonyl]-1-methyl-1H-pyrrole-2- carboxylate 167N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 518hydroxypropyl}-3,4-dimethoxybenzenesulfonamide 1685-chloro-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 498hydroxypropyl}thiophene-2-sulfonamide 169N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 544hydroxypropyl}-6-(morpholin-4-yl)pyridine-3-sulfonamide 170N-{2-chloro-4-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1- 549yl]-2-hydroxypropyl}amino)sulfonyl]phenyl}acetamide 171N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 542hydroxypropyl}-2,3-dihydroxyquinoxaline-6-sulfonamide 172N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 518hydroxypropyl}-2,4-dimethoxybenzenesulfonamide 1735-[({(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 531hydroxypropyl}amino)sulfonyl]-2-methoxybenzamide 174N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 472hydroxypropyl}-2-methylbenzenesulfonamide 175N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 493hydroxypropyl}-2,4-dimethyl-1,3-thiazole-5-sulfonamide 176N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 526hydroxypropyl}-2-hydroxyquinoxaline-6-sulfonamide 177N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 529hydroxypropyl}-4-methyl-3,4-dihydro-2H-1,4-benzoxazine-7- sulfonamide178 N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 459hydroxypropyl}pyridine-3-sulfonamide 1794′-cyano-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 559hydroxypropyl}biphenyl-2-sulfonamide 180N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 476hydroxypropyl}-1,2-dimethyl-1H-imidazole-4-sulfonamide 1814-acetyl-N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 500hydroxypropyl}benzenesulfonamide 182N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 536hydroxypropyl}-4-(methylsulfonyl)benzenesulfonamide 1832-chloro-4-cyano-N-{(2S)-3-[4-(3,4-dichlorophenoxy)-piperidin- 5171-yl]-2-hydroxypropyl}benzenesulfonamide 184N-{(2S)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2- 490hydroxypropyl}-1,3,5-trimethyl-1H-pyrazole-4-sulfonamide

EXAMPLE 185N-[(2R)-3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxamide

Prepared as described in Example 1 following Preparation 7 using4-oxo-1,4-dihydroquinoline-3-carboxylic acid.

MS (APCI) 490/492 (M+H)⁺

¹H NMR δ (DMSO) 10.21 (5H, t), 8.74 (6H, s), 8.26 (6H, dd), 7.74 (10H,ddd), 7.68 (8H, d), 7.49 (11H, d), 7.48-7.44 (1H, m), 7.25 (6H, d), 6.98(6H, dd), 4.80 (4H, s), 4.44 (6H, septet), 3.75 (6H, s), 3.55 (7H, ddd),3.26-3.19 (20H, m), 2.78-2.68 (12H, m), 2.34 (20H, d), 2.33-2.25 (24H,m), 1.96-1.88 (12H, m), 1.69-1.58 (12H, m).

EXAMPLE 186N-{(2S)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamideacetate salt

Prepared as described in Example 35 following Preparation 10 using(2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate and1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 470/472 (M+H)⁺

¹H NMR δ (DMSO) 8.32 (1H, t), 8.22 (2H, d), 7.73 (1H, td), 7.52 (1H,td), 7.52 (1H, s), 7.20 (1H, d), 7.14 (1H, dd), 6.98 (1H, d), 4.38 (1H,septet), 3.81 (1H, quintet), 3.43-3.36 (1H, m), 3.18-3.11 (1H, m),2.75-2.63 (2H, m), 2.42-2.28 (4H, m), 2.14 (3H, s), 1.94-1.84 (2H, m),1.88 (3H, s, OAc), 1.70-1.58 (2H, m).

EXAMPLE 187N-{(2S)-3-{4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 35 following Preparation 14 using1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 490/492/494 (M+H)⁺

¹H NMR δ (CD₃OD) 8.40 (1H, d), 8.21 (1H, d), 7.74 (1H, t), 7.54 (1H, t),7.50 s), 7.32 (1H, d), 7.00 (1H, d), 6.76 (1H, dd), 4.36-4.24 (1H, m),3.99-3.93 (1H, d), 3.73-3.68 (1H, d), 3.33-3.28 (1H, m), 2.96-2.84 (1H,m), 2.75-2.30 (5H, m), 2.04-1.94 (2H, m), 1.88-1.76 (2H, s).

EXAMPLE 188N-{(2S)-3-{4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 35-following Preparation 15 using1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 504/506/508 (M+H)⁺

¹H NMR δ (CD₃OD) 8.38 (1H, d), 8.19 (1H, d) 7.80 (1H, t), 7.61 (1H, t),7.60 (1H, t), 7.38 (1H, d), 7.09 (1H, d), 6.87 (1H, dd), 4.37-4.30 (1H,m), 3.64 (1H, d), 3.42 (1H, d), 3.03-2.83 (2H, m), 2.60-2.46 (4H, m),1.96-1.86 (2H, m), 1.72-1.60 (2H, m), 1.26 (3H, s).

EXAMPLE 189N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-[(methylamino)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

7-[(Methylamino)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid (0.1 g) in dimethyl formamide (7 ml) was treated withN,N-carbonyldiimidazole (0.06 g) and the mixture was heated at 55° C.for 45 min.(2R)-1-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.11g) in dimethyl formamide (1 ml) was added and the mixture was stirred atambient temperature for 18 h. 1 Drop of water was added and the solventwas evaporated. Purification using revere phase HPLC (Symmetry C8column) and acetonitrile/aqueous ammonium acetate as eluent yielded thetitle compound as a white solid (0.03 g).

MS (APCI) 583/585 (M+H)⁺

¹H NMR δ (DMSO) 8.59 (1H, s), 8.44 (1H, d), 8.42 (1H, t), 8.04 (1H, dd),7.73 (1H, s), 7.62 (1H, s), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd),4.79 (1H, s), 4.44 (1H, septet), 3.80 (1H, quintet), 3.45-3.37 (1H, m),3.18-3.11 (1H, m), 2.81-2.69 (2H, m), 2.42 (3H, s), 2.39-2.25 (4H, m),1.96-1.87 (2H, m), 1.66-1.55 (2H, m).

EXAMPLE 190N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-{[(2-hydroxyethyl)amino]sulfonyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamideacetate salt

Prepared as described in Example 189 following Preparation 7 using1,2-dihydro-7-[[(2-hydroxyethyl)amino]sulfonyl]-1-oxo-4isoquinolinecarboxylic acid.

MS (APCI) 613/615 (M+H)⁺

¹H NMR δ (DMSO) 8.61 (1H, s), 8.42 (1H, d), 8.07 (1H, dd), 7.71 (1H, s),7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, d), 4.44 (1H, septet), 3.81 (1H,quintet), 3.46-3.37 (1H, m), 3.35 (2H, t), 3.18-3.10 (1H, m), 2.80-2.68(2H, m), 2.80 (2H t), 2.42-2.25 (4H, m), 1.96-1.87 (2H, m), 1.88 (3H, s,OAc), 1.66-1.55 (2H, m).

EXAMPLE 1917-[(Cyclopropylamino)sulfonyl]-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 189 following Preparation 7 using7-[(cyclopropylamino)sulfonyl]-1,2-dihydro-1-oxo-4-isoquinolinecarboxylicacid.

MS (APCI) 609/611 (M+H)⁺

¹H NMR δ (DMSO) 8.64 (1H, s), 8.44 (1H, d), 8.41 (1H, t), 8.07 (1H, dd),7.72 (1H, s), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.78 (1H, s),4.44 (1H, septet), 3.81 (1H, quintet), 3.45-3.38 (1H, m), 3.18-3.10 (1H,m), 2.81-2.69 (2H, m), 2.42-2.25 (4H, m), 2.15-2.09 (1H, m), 1.96-1.86(2H, m), 1.66-1.54 (2H, m), 0.50-0.44 (2H, m), 0.38-0.32 (2H, m).

EXAMPLE 1927-(Azetidin-1-ylsulfonyl)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamideAcetate Salt

Prepared as described in Example 189 following Preparation 7 using7-(azetidin-1-ylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid.

MS (APCI) 609/611 (M+H)⁺

¹H NMR δ (DMSO) 8.53 (1H, t), 8.52 (1H, d), 8.44 (1H, t), 8.09 (1H, dd),7.77 (1H, s), 7.50 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.43 (1H,septet), 3.81 (1H, quintet), 3.69 (4H, t), 3.47-3.37 (1H, m), 3.21-3.10(1H, m), 2.83-2.68 (2H, m), 2.40-2.24 (4H, m), 2.05-1.86 (2H, m), 1.97(2H, quintet), 1.88 (3H, s, OAc), 1.68-1.53 (2H, m).

EXAMPLE 1937-(Aminosulfonyl)-N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 189 following Preparation 7 using7-(aminosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 569/571 (M+H)⁺

¹H NMR δ (DMSO) 8.65 (1H, s), 8.40 (1H, d), 8.39 (1H, t), 8.09 (1H, dd),7.69 (1H, s), 7.49 (1H, d), 7.50 (2H, s), 7.25 (1H, d), 6.98 (1H, dd),4.77 (1H, s), 4.44 (1H, septet), 3.85-3.77 (1H, m), 3.41 (1H, dt), 3.14(1H, dt), 2.81-2.69 (2H, m), 2.41-2.25 (4H, m), 1.96-1.86 (2H, m),1.67-1.54 (2H, m).

EXAMPLE 194N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-[(dimethylamino)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 189 following Preparation 7 using7-[(dimethylamino)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid

MS (APCI) 597/599 (M+H)⁺

¹H NMR δ (DMSO) 8.49 (1H, s), 8.48 (1H, d), 8.43 (1H, t), 8.04 (1H, dd),7.75 (1H, s), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.44 (1H,septet), 3.81 (1H, quintet), 3.46-3.37 (1H, m), 3.18-3.11 (1H, m),2.82-2.69 (2H, m), 2.64 (6H, s), 2.42-2.26 (4H, m), 1.95-1.86 (2H, m),1.89 (3H, s, OAc), 1.60 (2H, dt).

EXAMPLE 195N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-[(3-hydroxy-3-methylazetidin-1-yl)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxamideacetate salt

Prepared as described in Example 189 following Preparation 7 using7-[(3-hydroxy-3-methylazetidin-1-yl)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid.

MS (APCI) 639/641 (M+H)⁺

¹H NMR δ (DMSO) 8.53 (1H, d), 8.51 (1H, d), 8.45 (1H, t), 8.08 (1H, dd),7.77 (1H, s), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd), 4.44 (1H,septet), 3.82 (1H, quintet), 3.60 (2H, d), 3.45 (2H, d), 3.45-3.40 (1H,m), 3.19-3.10 (1H, m), 2.81-2.69 (2H, m), 2.42-2.25 (4H, m), 1.96-1.84(2H, m), 1.88 (3H, s, OAc), 1.66-1.55 (2H, m).

EXAMPLE 196N-[(2R)-3-(4-{3,4-Dichloro-2-[(cyclopropylamino)carbonyl]phenoxy}piperidin-1-yl)-2-hydroxypropyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxamideacetate salt

Prepared as described in Example 35 following Preparation 35 using1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 573/575 (M+H)⁺

¹H NMR δ (CD₃OD) 8.25 (1H, d), 8.09 (1H, d), 7.68 (1H, t), 7.49 (1H, s),7.48 (1H, t), 7.38 (1H, d), 6.97 (1H, d), 4.54-4.48 (1H, m), 4.03-3.97(1H, m), 3.44 (1H, dd), 3.30 (1H, dd), 2.90-2.79 (2H, m), 2.76-2.58 (5H,m), 1.98-1.89 (2H, m), 1.87-1.79 (2H, m), 1.85 (3H, s, OAc), 0.70-0.65(2H, m), 0.52-0.48 (2H, m).

EXAMPLE 197N-{(2R)-3-[4-(3-Chloro-4-cyanophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 35 following Preparation 24 using1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 481 (M+H)⁺

¹H NMR δ (CD₃OD) 8.36 (1H, dd), 8.19 (1H, d), 7.86 (2H, d), 7.77-7.75(2H, m), 7.57 (2H, td), 7.12 (2H, d), 4.62-4.56 (1H, m), 4.07-4.01 (1H,m), 3.57 (1H, dd), 3.38 (1H, dd), 3.08 (3H, s), 2.98-2.88 (2H, m),2.66-2.55 (4H, m), 2.12-2.04 (2H, m), 1.92-1.83 (2H, m).

EXAMPLE 198N-((2R)-2-Hydroxy-3-{4-[4-(methylsulfonyl)phenoxy]piperidin-1-yl}propyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 35 following Preparation 25 using1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 500 (M+H)⁺

¹H NMR δ (CD₃OD) 8.36 (1H, dd), 8.19 (1H, d), 7.86 (2H, d), 7.77-7.75(2H, m), 7.57 (2H, td), 7.12 (2H, d), 4.62-4.56 (1H, m), 4.07-4.01 (1H,m), 3.57 (1H, dd), 3.38 (1H, dd), 3.08 (3H, s), 2.98-2.88 (2H, m),2.66-2.55 (4H, m), 2.12-2.04 (2H, m), 1.92-1.83 (2H, m).

EXAMPLE 199N-{(2R)-3-[4-(4-Cyanophenoxy)piperidin-1-yl]-2-hydroxypropyl}-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 35 following Preparation 26 using1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 447 (M+H)⁺

¹H NMR δ (DMSO) 8.31 (1H, t), 8.22 (2H, d), 7.75-7.71 (3H, m), 7.54-7.50(2H, m), 7.12 (2H, d), 4.80-4.73 (1H, m), 4.56-4.49 (1H, m), 3.83-3.77(1H, m), 3.42-3.35 (2H, m), 3.18-3.11 (1H, m), 2.81-2.71 (2H, m),2.41-2.27 (4H, m), 1.98-1.91 (2H, m), 1.68-1.59 (2H, m).

EXAMPLE 200N-((2R)-3-{4-[2-(Aminocarbonyl)-4-chlorophenoxy]piperidin-1-yl}-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 35 following Preparation 33 using3-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 499 (M+H)⁺

¹H NMR δ (CD₃OD) 8.25 (1H, d), 8.08 (1H, d), 7.78 (1H, d), 7.467 (1H,td), 7.48 (1H, t), 7.47 (1H, s), 7.35 (1H, dd), 7.08 (1H, d), 4.56-4.50(1H, m), 3.94-3.89 (1H, m), 3.46 (1H, dd), 3.27 (1H, dd), 2.79-2.70 (2H,m), 2.46-2.36 (4H, m), 2.03-1.95 (2H, m), 1.82-1.73 (2H, m).

EXAMPLE 201N-[(2R)-3-(4-{4-Chloro-2-[(methylamino)carbonyl]phenoxy}piperidin-1-yl)-2-hydroxypropyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 35 following Preparation 32 using1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 513 (M+H)⁺

¹H NMR δ (CD₃OD) 8.25 (1H, d), 8.09 (1H, d), 7.67 (1H, td), 7.63 (1H,d), 7.48 (1H, s), 7.48 (1H, td), 7.33 (1H, dd), 7.07 (1H, d), 4.59-4.51(1H, m), 4.01-3.94 (1H, m), 3.46 (1H, dd), 3.28 (1H, dd), 2.91-2.80 (2H,m), 2.83 (3H, s), 2.66-2.54 (4H, m), 2.05-1.94 (2H, m), 1.90-1.79 (2H,m).

EXAMPLE 202 Methyl5-chloro-2-{[1-((2R)-2-hydroxy-3-{[(1-oxo-1,2-dihydroisoquinolin-4-yl)carbonyl]amino}propyl)piperidin-4-yl]oxy}benzoateacetate salt

Prepared as described in Example 35 following Preparation 31 using1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 513 (M+H)⁺

¹H NMR δ (CD₃OD) 8.25 (1H, dd), 8.09 (1H, d), 7.67 (1H, td), 7.60 (1H,d) (1H, s), 7.48 (1H, td), 7.38 (1H, dd), 7.06 (1H, d), 4.59-4.54 (1H,m), 4.05-3.99 (1H, m), 3.76 (3H, s), 3.45 (1H, dd), 3.30 (1H, dd),3.03-2.92 (2H, m), 2.79-2.61 (4H, m), 2.00-1.86 (4H, m), 1.84 (3H, s,OAc).

EXAMPLE 203N-((2R)-3-{4-[2-(Aminosulfonyl)-3,4-dichlorophenoxy]piperidin-1-yl}-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamidetrifluoroacetate salt

Prepared as described in Example 35 following Preparation 40 using1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 569/571 (M+H)⁺

¹H NMR δ (CD₃OD) 8.26 (1H, d), 8.09 (1H, d), 7.71 (1H, t), 7.62 (1H, d),7.52 (1H, s), 7.48 (1H, t), 7.18 (1H, d), 5.02 (1H, s), 4.23-4.15 (1H,m), 3.55 (1H, m), 3.46-3.33 (5H, m), 3.16-3.08 (2H, m), 2.26 (2H, t),2.15-2.00 (2H, m).

EXAMPLE 204N-[(2R)-3-(4-{3,4-Dichloro-2-[(methylamino)sulfonyl]phenoxy}piperidin-1-yl)-2-hydroxypropyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxamideacetate salt

Prepared as described in Example 35 following Preparation 41 using1-oxo-1,2-dihydroisoquinoline 4 carbonyl chloride.

MS (APCI) 583/585 (M+H)⁺

¹H NMR δ (CD₃OD) 8.25 (1H, d), 8.08 (1H, d), 7.69 (1H, td), 7.60 (1H,d), 7.49 (1H, s), 7.48 (1H, td), 7.16 (1H, d), 4.73-4.68 (1H, m),4.05-3.99 (1H, m), 3.44 (1H, dd), 3.30 (1H, dd), 3.15-3.04 (2H, m),2.78-2.63 (4H, m), 2.52 (3H, s), 2.07-1.93 (4H, m), 1.85 (3H, s, OAc).

EXAMPLE 205N-[(2R)-3-(4-{3,4-Dichloro-2-[(cyclopropylamino)sulfonyl]phenoxy}piperidin-1-yl)-2-hydroxypropyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxamideacetate salt

Prepared as described in Example 35 following Preparation 42 using1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 609/611 (M+H)⁺

¹H NMR δ (CD₃OD) 8.25 (1H, d), 8.08 (1H, d), 7.68 (1H, t), 7.61 (1H, d),7.49 (1H, s), 7.47 (1H, t), 7.17 (1H, d), 4.72-4.65 (1H, m), 4.03-3.96(1H, m), 3.44 (1H, dd), 3.30 (1H, dd), 3.11-2.99 (2H, m), 2.73-2.58 (4H,m), 2.19-2.13 (1H, m), 2.04-1.90 (4H, m), 1.83 (3H, s, OAc), 0.50-0.43(4H, m).

EXAMPLE 206N-{(2R)-3-[4-(3-Chloro-4-cyanophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 189 following Preparation 24 using7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 559 (M+H)⁺

¹H NMR δ (CD₃OD) 8.78 (1H, d), 8.35 (1H, d), 8.14 (1H, dd), 7.68 (1H,s), 7.60 (1H, d), 7.12 (1H, d), 6.95 (1H, dd), 4.56-4.51 (1H, m),4.01-3.95 (1H, m), 3.47 (1H, dd), 3.28 (1H, dd), 3.10 (3H, s), 2.94-2.85(2H, m), 2.64-2.52 (4H, m), 2.04-1.95 (2H, m), 1.86 (3H, s), 1.83-1.74(2H, m).

EXAMPLE 207N-{(2R)-3-{4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxy-2-methylpropyl}-6-(methylsulphonyl)-1H-indole-3-carboxamide

Prepared as described in Example 189 following Preparation 10 using6-(methylsulphonyl)-1H-indole-3-carboxylic acid.

MS (APCI) 520/522/524 (M+H)⁺

¹H NMR δ (CD₃OD) 8.35 (1H, d), 8.19 (1H, s), 8.07 (1H, d), 7.69 (1H,dd), 7.11 (1H, d), 7.08 (1H, dd), 6.88 (1H, d), 4.56-4.48 (1H, m),4.20-4.12 (1H, m), 3.57 (1H, dd), 3.43 (1H, dd), 3.19-3.12 (5H, s),3.03-2.98 (2H, m), 2.94 (1H, dd), 2.85 (1H, m), 2.18 (3 h, s), 2.16-2.08(2H, m), 2.03-1.94 (2H, m).

EXAMPLE 208N-{(2R)-3-{4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-(methylsulphonyl)-1H-indole-3-carboxamide

Prepared as described in Example 189 following Preparation 8 using6-(methylsulphonyl)-1H-indole-3-carboxylic acid.

MS (APCI) 540/542/544 (M+H)⁺

¹H NMR δ (CD₃OD) 8.35 (1H, d), 8.34 (1H, s), 8.06 (1H, d), 7.69 (1H,dd), 7.38 (1H, d), 7.09 (1H, d), 6.87 (1H, dd), 4.50-4.43 (1H, m),4.12-4.06 (1H, m), 3.57 (1H, dd), 3.41 (1H, dd), 3.13 (3H, s), 3.07-2.99(2H, m), 2.81-2.68 (4H, m), 2.12-2.04 (2H, m), 1.94-1.82 (2H, m).

EXAMPLE 209N-{(2R)-3-[(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 189 following Preparation 7 using7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 508/510 (M+H)⁺

¹H NMR δ (DMSO) 11.73 (1H, s), 8.39-8.26 (2H, m), 7.88 (1H, dd), 7.64(1H, td), 7.54 (1H, s), 7.49 (1H, d), 7.25 (1H, d), 6.98 (1H, dd),4.79-4.71 (1H, m), 4.48-4.38 (1H, m), 3.85-3.75 (1H, m), 3.46-3.34 (1H,m), 3.19-3.09 (1H, m), 2.82-2.65 (2H, m), 2.43-2.23 (4H, m), 1.97-1.84(2H, m), 1.67-1.53 (2H, m).

EXAMPLE 210N-{(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 189 following Preparation 10 using7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 488 (M+H)⁺

¹H NMR δ (DMSO) 8.42-8.28 (2H, m), 7.88 (1H, dd), 7.64 (1H, td), 7.55(1H, s), 7.20 (1H, d), 7.14 (1H, dd), 6.98 (1H, d), 4.43-4.33 (1H, m),3.85-3.75 (1H, m), 3.45-3.34 (1H, m), 3.20-3.08 (1H, m), 2.75-2.60 (2H,m), 2.42-2.25 (4H, m), 2.14 (3H, s), 1.94-1.81 (2H, m), 1.70-1.56 (2H,m).

EXAMPLE 211N-{(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 189 following Preparation 10 using6-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 548 (M+H)⁺

¹H NMR δ (DMSO) 11.98 (1H, s), 8.89 (1H, d), 8.44 (1H, d), 8.42 (1H, t),8.01 (1H, dd), 7.76-7.72 (1H, m), 7.20 (1H, d), 7.14 (1H, dd), 6.98 (1H,d), 4.77 (1H, d), 4.43-4.34 (1H, m), 3.86-3.77 (1H, m), 3.42 (1H, td),3.28 (3H, s), 3.17 (1H, quintet), 2.77-2.63 (2H, m), 2.42-2.29 (4H, m),2.14 (3H, s), 1.95-1.84 (2H, m), 1.71-1.58 (2H, m).

EXAMPLE 212N-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 189 following Preparation 13 using6-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 581/583 (M+H)⁺

¹H NMR δ (DMSO) 11.97 (1H, d), 8.89 (1H, d), 8.44 (1H, d), 8.42 (1H, t),8.01 (1H, dd), 7.76-7.72 (1H, m), 7.35 (1H, d), 7.10 (1H, d), 4.80-4.73(1H, m), 4.53-4.44 (1H, m), 3.86-3.76 (1H, m), 3.42 (1H, td), 3.28 (3H,s), 3.21-3.12 (1H, m), 2.79-2.65 (2H, m), 2.40 (3H, s), 2.42-2.30 (4H,m), 1.95-1.85 (2H, m), 1.74-1.61 (2H, m).

EXAMPLE 213N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamideacetate salt

Prepared as described in Example 189 following Preparation 7 using7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 568/566 (M+H)⁺

¹H NMR δ (DMSO) 8.70 (1H, s), 8.46 (1H, d), 8.16 (1H, dd), 8.10 (1H, t),7.70 (1H, s), 7.45 (1H, d), 7.18 (1H, d), 6.94 (1H, dd), 4.39 (1H,septet), 3.82 (1H, quintet), 3.42 (1H, dt), 3.30-3.09 (1H, m), 3.22 (3H,s), 2.82-2.67 (2H, m), 2.45-2.27 (4H, m), 1.99-1.80 (2H, m), 1.89 (3H,s, OAc), 1.72-1.53 (2H, m).

EXAMPLE 214N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamideacetate salt

Prepared as described in Example 189 following Preparation 10 using7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 548/550 (M+H)⁺

¹H NMR δ (DMSO) 8.68 (1H, d), 8.48 (1H, d), 8.43 (1H, t), 8.20 (1H, dd),7.76 (1H, s), 7.21 (1H, d), 7.15 (1H, dd), 6.98 (1H, d), 4.84-4.72 (1H,m), 4.46-4.31 (1H, m), 3.88-3.74 (1H, m), 3.49-3.34 (1H, m), 3.28 (3H,s), 3.22-3.08 (1H, m), 2.78-2.60 (2H, m), 2.44-2.24 (4H, m), 2.14 (3H,s), 1.98-1.79 (2H, m), 1.74-1.54 (2H, m).

EXAMPLE 215N-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamideacetate salt

Prepared as described in Example 189 following Preparation 13 using7-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 582/584 (M+H)⁺

¹H NMR δ (DMSO) 8.68 (1H, d), 8.47 (1H, d), 8.44 (1H, t), 8.20 (1H, dd),7.76 (1H, s), 7.35 (1H, d), 7.10 (1H, d), 4.53-4.44 (1H, m), 3.81 (1H,quintet), 3.42 (1H, dt), 3.20-3.09 (1H, m), 2.77-2.65 (2H, m), 2.40 (3H,s), 2.39-2.28 (4H, m), 1.95-1.85 (2H, m), 1.87 (3H, s, OAc), 1.73-1.61(2H, m).

EXAMPLE 216N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 189 following Preparation 7 using6-(methylsulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (ESI) 568/570 (M+H)⁺

EXAMPLE 217N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 189-following Preparation 7 using6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (APCI) 508/510 (M+H)⁺

¹H NMR δ (DMSO) 11.70 (1H, d), 8.34 (1H, t), 8.28 (1H, dd), 8.03 (1H,dd), 7.64 (1H, d), 7.49 (1H, d), 7.38 (1H, td), 7.25 (1H, d), 6.98 (1H,dd), 4.80-4.70 (1H, m), 4.44 (1H, septet), 3.87-3.73 (1H, m), 3.45-3.36(1H, m), 3.14 (1H, quintet), 2.84-2.66 (2H, m), 2.43-2.21 (4H, m),1.99-1.84 (2H, m), 1.69-1.51 (2H, m).

EXAMPLE 218N-{(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 189 following Preparation 10 using6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid.

MS (ESI) 488/490 (M+H)⁺

EXAMPLE 219N-{(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-oxo-4-(trifluoromethyl)-1,2-dihydropyrimidine-5-carboxamide

Prepared as described in Example 35 following Preparation 10 using2-oxo-4-(trifluoromethyl)-1,2-dihydropyrimidine-5-carbonyl chloride.

MS (ESI) 489/491 (M+H)⁺

EXAMPLE 220N-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-oxo-4-(trifluoromethyl)-1,2-dihydropyrimidine-5-carboxamide

Prepared as described in Example 35 following Preparation 13 using2-oxo-4-(trifluoromethyl)-1,2-dihydropyrimidine-5-carbonyl chloride.

MS (ESI) 523/525 (M+H)⁺

EXAMPLE 221N-((2R)-3-{4-[3,4-Dichloro-2-(methylsulfonyl)phenoxy]piperidin-1-yl}-2-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamideacetate

Prepared as described in Example 35 following Preparation 48 using1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 568/570 (M+H)⁺

¹H NMR δ (CD₃OD) 8.35 (1H, d), 8.18 (1H, d), 7.78 (1H, t), 7.76 (1H, d),7.58 (1H, s), 7.57 (1H, t), 7.28 (1H, d), 4.87-4.80 (1H, m), 4.13-4.07(1H, m), 3.54 (1H, dd), 3.40 (1H, dd), 3.35 (3H, s), 3.16-3.06 (2H, m),2.85-2.69 (4H, m), 2.16-2.00 (4H, m), 1.94 (3H, s).

EXAMPLE 222N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamideacetate salt

Prepared as described in Example 35 following Preparation 7 using6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carbonyl chloride, whichwas prepared by hydrolysis with sodium hydroxide followed by treatmentwith thionyl chloride of the commercially available 6-chloro1-trifluoromethyl methyl nicotinoate).

MS (APCI) 508/510 (M+H)⁺

¹H NMR δ (DMSO) 8.35 (1H, t), 7.77 (1H, s), 7.49 (1H, d), 7.25 (1H, d),6.98 (1H, dd), 6.72 (1H, s), 4.43 (1H, septet), 3.71 (1H, quintet), 3.29(1H, dt), 3.06 (1H, dt), 2.78-2.66 (2H, m), 2.36-2.24 (4H, m), 1.95-1.86(2H, m), 1.90 (3H, s), 1.65-1.54 (2H, m).

EXAMPLE 223N-{(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamideacetate salt

Prepared as described in Example 35 following Preparation 10 using6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carbonyl chloride.

MS (APCI) 488/490 (M+H)⁺

¹H NMR δ (DMSO) 8.35 (1H, t), 7.77 (1H, s), 7.20 (1H, s), 7.15 (1H, dd),6.98 (1H, d), 6.73 (1H, s), 4.42-4.34 (1H, m), 3.72 (1H, quintet),3.33-3.27 (1H, m), 3.06 (1H, dt), 2.71-2.61 (2H, m), 2.37-2.25 (4H, m),2.14 (3H, s), 1.93-1.84 (2H, m), 1.91 (3H, s), 1.69-1.58 (2H, m).

EXAMPLE 224N-{(2R)-3-[4-(2,4-Dichloro-3-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide

Prepared as described in Example 35 following Preparation 13 using6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carbonyl chloride.

MS (APCI) 522/524 (M+H)⁺

¹H NMR δ (DMSO) 8.32 (1H, t), 7.79 (1H, s), 7.35 (1H, d), 7.10 (1H d),6.69 (1H, s), 4.49 (1H, septet), 3.72 (1H, quintet), 3.30 (1H, dt), 3.07(1H, dt), 2.74-2.64 (2H, m), 2.40 (3H, s), 2.37-2.25 (4H, m), 1.94-1.84(2H, m), 1.89 (3H, s), 1.71-1.61 (2H, m).

EXAMPLE 225N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-(2-oxoquinoxalin-1(2H)-yl)acetamide

Prepared as described in Example 1 following Preparation 7 using(2-oxo-quinoxalin-1-(2H)-yl)acetic acid.

MS (APCI) 505/507 (M+H)⁺

¹H NMR δ (CDCl₃) 8.37 (1H, s), 7.92 (1H, d), 7.61 (1H, t), 7.49 (1H, d),7.40 (1H, t), 7.32 (1H, d), 6.99 (1H, d), 6.74 (1H, dd), 6.72 (1H, bds), 4.91 (2H, m), 4.36-4.26 (1H, m), 3.86-3.76 (1H, m), 3.52-3.42 (1H,m), 3.26-3.18 (1H, m), 2.88-2.80 (1H, m), 2.63-2.53 (2H, m), 2.40-2.26(3H, m), 2.06-1.92 (2H, m), 1.87-1.73 (2H, m).

EXAMPLE 226N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide

Prepared as described in Example 35 following Preparation 7 using3-oxo-3,4-dihydroquinoxaline-1(2H)-carbonyl chloride.

MS (APCI) 505/507 (M+H)⁺

¹H NMR δ (CDCl₃) 8.26 (1H, s), 7.43 (1H, d), 7.31 (1H, d), 7.19-7.09(1H, m), 6.99 (1H, d), 6.94 (1H, d), 6.75 (1H, dd), 5.72 (1H, t), 4.44(2H, s), 4.30-4.22 (1H, m), 3.88-3.81 (1H, m), 3.58-3.52 (1H, m),3.17-3.11 (1H, m), 2.93-2.85 (1H, m), 2.67-2.61 (1H, m), 2.57-2.53 (1H,m), 2.44-2.40 (1H, m), 2.36-2.29 (2H, m), 2.00-1.90 (2H, m), 1.80-1.70(2H, m).

EXAMPLE 227N-{(2R)-3-[4-(4-Chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide

Prepared as described in Example 1 following Preparation 10 using3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid.

MS (APCI) 460/462 (M+H)⁺

¹H NMR δ (DMSO) 8.41 (1H, s), 8.15 (1H, t), 7.20 (1H, d), 7.14 (1H, dd),6.98 (1H, d), 4.42-4.36 (1H, m), 3.77-3.71 (1H, m), 3.39-3.33 (1H, m),3.10-3.04 (1H, m), 2.73-2.63 (2H, m), 2.36-2.26 (4H, m), 2.14 (3H, s),1.92-1.82 (2H, m), 1.70-1.60 (2H, m).

EXAMPLE 228N-{(2R)-3-[4-(2,4-dichloro-3-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide

Prepared as described in Example 1 following Preparation 13 using3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid.

MS (APCI) 495/497 (M+H)⁺

¹H NMR δ (DMSO) 8.41 (1H, s), 8.15 (1H, t), 7.34 (1H, d), 7.09 (1H, dd),4.50-4.42 (1H, m), 3.77-3.71 (1H, m), 3.37-3.33 (1H, m), 3.10-3.04 (1H,m), 2.74-2.64 (2H, m), 2.39 (3H, s), 2.36-2.26 (4H, m), 1.96-1.86 (2H,m), 1.69-1.62 (2H, m).

EXAMPLE 229N-{(2R)-3-{4-(3,4-Dichlorophenoxy)piperidin-1-yl}-2-hydroxypropyl}-1-oxo-1,2-dihydro-2-methylisoquinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 7 using2-methyl-1-oxo-1,2-dihydroisoquinoline-carboxylic acid.

MS (APCI) 504/506/508 (M+H)⁺

¹H NMR δ (CDCl₃) 8.47 (1H, d), 8.14 (1H, d), 7.70 (1H, t), 7.61 (1H, s),7.53 (1H, t), 7.33 (1H, d), 7.00 (1H, d), 6.76 (1H, dd), 6.58 (1H, bdt), 4.42-4.32 (1H, m), 4.06-3.96 (1H, m), 3.80-3.70 (1H, m), 3.63 (3H,s), 3.44-3.34 (1H, m), 3.02-2.92 (1H, m), 2.78-2.68 (2H, m), 2.59-2.45(3H, m), 2.16-2.00 (2H, m), 1.96-1.80 (2H, m).

EXAMPLE 230N-{(2R)-3-{4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-oxo-1,2-dihydro-1-methylquinoline-4-carboxamide

Prepared as described in Example 1 following Preparation 7 using1-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid.

MS (APCI) m/z 504/506/508 (M+H)⁺

¹H NMR δ (CDCl₃) 7.97 (1H, d), 7.62 (1H, t), 7.40 (1H, d), 7.32 (1H, d),7.28 (1H, t), 7.00 (1H, d), 6.83 (1H, s), 6.76 (1H, dd), 6.72 (1H, t),4.39-4.31 (1H, m), 4.04-3.94 (1H, m), 3.78-3.70 (1H, m), 3.72 (3H, s),3.47-3.37 (1H, m), 3.00-2.90 (1H, m), 2.75-2.67 (2H, m), 2.56-2.42 (3H,m), 2.10-1.94 (2H, m), 1.94-1.78 (2H, m).

EXAMPLE 231N-{(2R)-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 35 following Preparation 7 using8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 508/510 (M+H)⁺

EXAMPLE 232N-{(2R)-3-[4-(4-chloro-2-methylphenoxy)piperidin-1-yl]-2-hydroxypropyl}-8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

Prepared as described in Example 35 following Preparation 10 using8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carbonyl chloride.

MS (APCI) 488/490 (M+H)⁺

EXAMPLE 233N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-2-oxo-4-(trifluoromethyl)-1,2-dihydropyrimidine-5-carboxamide

Prepared as described in Example 35 following Preparation 7 using2-oxo-4-(trifluoromethyl)-1,2-dihydropyrimidine-5-carbonyl chloride.

MS (EPCI) 509/511 (M+H)⁺

EXAMPLE 234N-{(2R)-3-[4-(3,4-Dichlorophenoxy)piperidin-1-yl]-2-hydroxypropyl}-4-methyl-2-oxo-1,2-dihydropyrimidine-5-carboxamide

Prepared as described in Example 35 following Preparation 7 using4-methyl-2-oxo-1,2-dihydropyrimidine-5-carbonyl chloride.

MS (EPCI) 455/457 (M+H)⁺

EXAMPLE 235 Pharmacological Analysis: Calcium Flux [Ca²⁺]_(i) assay.

Human Eosinophils

Human eosinophils were isolated from EDTA anticoagulated peripheralblood as previously described (Hansel et al., J. Immunol. Methods, 1991,145, 105-110). The cells were resuspended (5×10⁶ ml⁻¹) and loaded with 5μM FLUO-3/AM+Pluronic F127 2.2 μl/ml (Molecular Probes) in lowpotassium-solution (LKS; NaCl 118 mM, MgSO₄ 0.8 mM; glucose 5.5 mM,Na₂CO₃ 8.5 mM, KCl 5 mM, HEPES 20 mM, CaCl₂ 1.8 mM, BSA 0.1%, pH 7.4)for one hour at room temperature. After loading, cells were centrifugedat 200 g for 5 min and resuspended in LKS at 2.5×10⁶ ml⁻¹. The cellswere then transferred to 96 well FLIPr plates (Poly-D-Lysine plates fromBecton Dickinson pre-incubated with 5 μM fibronectin for twoh) at 25μl/well. The plate was centrifuged at 200 g for 5 min and the cells werewashed twice with LKS (200 μl; room temperature).

A compound of the Examples was pre-dissolved in DMSO and added to afinal concentration of 0.1%(v/v) DMSO. Assays were initiated by theaddition of an A₅₀ concentration of eotaxin and the transient increasein fluo-3 fluorescence (1_(Ex)=490 nm and 1_(Em)=520 nm) monitored usinga FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices,Sunnyvale, U.S.A.).

Compounds of the Examples were found to be antagonists if the increasein fluorescence induced by eotaxin (a selective CCR3 agonist) wasinhibited in a concentration dependent manner. The concentration ofantagonist Expired to inhibit the fluorescence by 50% can be used todetermine the IC₅₀ for the antagonist at the CCR3 receptor.

EXAMPLE 236 Human Eosinophil Chemotaxis

Human eosinophils were isolated from EDTA anticoagulated peripheralblood as previously described (Hansel et al., J. Immunol. Methods, 1991,145, 105-110). The cells were resuspended at 10×10⁶ ml⁻¹ in RPMIcontaining 200 IU/ml penicillin, 200 μg/ml streptomycin sulfate andsupplemented with 10% SACS, at room temperature.

Eosinophils (700 μl) were pre-incubated for 15 mins at 37° C. with 7 μlof either vehicle or compound 100× required final concentration in 10%DMSO). The chemotaxis plate (ChemoTX, 3 μm pore, Neuroprobe) was loadedby adding 28 μl of a concentration of eotaxin 0.1 to 100 nM (a selectiveCCR3 agonist over this concentration range) containing a concentrationof a compound according to the Examples or solvent to the lower wells ofthe chemotaxis plate. The filter was then placed over the wells and 25+to of eosinophil suspension were added to the top of the filter. Theplate was incubated for 1 hr at 37° C. in a humidified incubator with a95% air/5% CO₂ atmosphere to allow chemotaxis.

The medium, containing cells that had not migrated, was carefullyaspirated from above the filter and discarded. The filter was washedonce with phosphate buffered saline (PBS) containing 5 mM EDTA to removeany adherent cells. Cells that had migrated through the filter werepelleted by centrifugation (300×g for 5 mins at room temperature) andthe filter removed and the supernatant transferred to each well of a96-well plate (Costar). The pelleted cells were lysed by the addition of28 μl of PBS-containing 0.5% Triton×100 followed by two cycles offreeze/thawing. The cell lysate was then added to the supernatant. Thenumber of eosinophils migrating was quantified according to the methodof Strath et. al., J. Immunol. Methods, 1985, 83, 209 by measuringeosinophil peroxidase activity in the supernatant.

Compounds of the Examples were found to be antagonists of eotaxinmediated human eosinophil chemotaxis if the concentration response toeotaxin was shifted to the right of the control curve. Measuring theconcentration of eotaxin required to give 50% chemotaxis in the presenceor absence of compounds enables the apparent affinity of the compoundsat CCR3 to be calculated, or the assay can be used to determine activityof compounds at a set concentration of compound against a predefinedconcentration of eotaxin.

% inhibition at 3 nM eotaxin Example (1 uM compound) 10 106 17 103 45102 46 105 47 104 52 95 53 105 58 104 132 101 186 104 192 103 197 103206 99 212 103 215 103 227 103

EXAMPLE 237 Guinea-Pig Isolated Trachea

(See for example, Harrison, R. W. S., Carswell, H. & Young, J. M. (1984)European J. Pharmacol., 106, 405-409.)

Male albino Dunkin-Hartley guinea-pigs (250 g) were killed by cervicaldislocation and the whole trachea removed. After clearing the adherentconnective tissue, the trachea was cut into six ring segments each threecartilage bands wide and then suspended in 20 ml organ baths containingKrebs-Henseleit solution of the following composition (mM): NaCl 117.6,NaH₂PO₄ 0.9, NaHCO₃ 25.0, MgSO₄ 1.2, KCl 5.4, CaCl₂ 2.6 and glucose11.1. The buffer was maintained at 37° C. and gassed with 5% CO₂ inoxygen. Indometacin (2.8 μM) was added to the Krebs solution to preventdevelopment of smooth muscle tone due to the synthesis ofcyclo-oxygenase products. The tracheal rings were suspended between twoparallel tungsten wire hooks, one attached to an Ormed beam isometricforce transducer and the other to a stationary support in the organbath. Changes in isometric force were recorded on 2-channel Sekonic flatbed chart recorders.

Experimental Protocols

At the beginning of each experiment a force of 1 g was applied to thetissues and this was reinstated over a 60 minute equilibration perioduntil a steady resting tone was achieved. Subsequently, a cumulativehistamine concentration effect (E/[A]) curve was constructed at 0.5log₁₀ unit increments, in each tissue. The tissues were then washed andapproximately 30 minutes later, test compound or vehicle (20% DMSO) wasadded. Following an incubation period of 60 minutes a second E/[A] curvewas performed to histamine.

Contraction responses were recorded as a percentage of the first curvemaximum.

Data Analysis

Experimental E/[A] curve data were analysed for the purposes ofestimating the potencies (p[A₅₀] values) of histamine in the absence andpresence of the test compound. Affinity (pA₂) values of test compoundswere subsequently-calculated using the following equation:log(r−1)=log [B]+pA₂where r=[A]₅₀ in presence of test compound/A]₅₀ in absence of antagonistand [B] is the concentration of test compound. Compounds of the Exampleswere found to be H1 antagonists.

EXAMPLE 238

Histamine H1 receptor binding activity of compounds of the invention wasassessed by competition displacement of 1 nM [3H]-pyrilamine (Amersham,Bucks, Product code TRK 608, specific activity 30 Ci/mmol) to 2 μgmembranes prepared from recombinant CHO-K1 cells expressing the human H1receptor (Euroscreen SA, Brussels, Belgium, product code ES-390-M) inassay buffer (50 mM Tris pH 7.4 containing 2 nM MgCl₂, 250 mM sucroseand 100 mM NaCl) for 1 hour at room temperature.

Example H1 pKi/[1328_S] 10 8.4 17 8.1 45 7.7 46 8.2 47 8.1 52 8.4 53 8.158 7.2 132 6.6 186 7.9 192 8.7 197 6.8 206 6.6 212 7.8 215 7.3 227 7.6

1. A compound of formula (I):

wherein: X is O; Y is a bond; Z is C(O); R¹ is phenyl optionallysubstituted by halogen, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy,S(O)₂(C₁₋₄alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂NH(C₃₋₆cycloalkyl), C(O)₂(C₁₋₄ alkyl), C(O)NH(C₁₋₄ alkyl) or C(O)NH₂; R⁴ ishydrogen, C₁₋₆ alkyl (optionally substituted by C₃₋₆ cycloalkyl) or C₃₋₆cycloalkyl; R², R³, R⁵, and R⁶ are, independently, hydrogen, C₁₋₆ alkylor C₃₋₆ cycloalkyl; m and n are both 0; R⁹ is aryl or heterocyclyl, eachof which is unsubstituted or substituted by one or more of: oxo (wherepossible), halogen, C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, S(O)₂(C₁₋₄ alkyl),S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ or OCF₃; R³² ishydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; or an N-oxide thereof; or apharmaceutically acceptable salt thereof.
 2. A compound as claimed inclaim 1, wherein R³² is hydrogen.
 3. A compound as claimed in claim 1wherein R², R³, R⁴, R⁵, and R⁶ are all hydrogen.
 4. A compound asclaimed in claim 1 wherein R⁹ is optionally substituted heterocyclyl;wherein the heterocyclyl group is: thienyl, pyrrolyl, thiazolyl,pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, 1,2,5-oxadiazolyl,pyridinyl, 1,6-dihydropyridinyl, pyrimidinyl, indolyl, indazolyl,2,3-dihydro-1H-indazolyl, an imidazopyridinyl, 2,1,3-benzothiadiazolyl,quinoxalinyl, quinolinyl, 1,2-dihydroquinolinyl, 1,4-dihydroquinoline,isoquinolinyl, 1,2-dihydroisoquinolinyl, cinnolinyl,3,4-dihydrophthalazinyl, 2,3-dihydro-4H-1,4-benzoxazinyl,3,4-dihydro-2H-1,4-benzoxazinyl, 1,3-dihydro-2H-isoindolyl,pyrazolotriazinyl, pyrazolopyrimidinyl, imidazobenzothiazolyl,imidazopyrimidinyl, or 2,1,3-benzoxadiazolyl, 1,3-benzothiazole,2,3-dihydro-1,3-benzothiazole, 4,5,6,7-tetrahydroindazole or2,3-dihydro-1H-benzimidazole; wherein the heterocyclyl is unsubstitutedor substituted by one or more of: oxo (where possible), halogen, C₁₋₄alkyl, CF₃, C₁₋₄ alkoxy, S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄alkyl), S(O)₂N(C₁₋₄ alkyl)₂ or OCF₃.
 5. A process for preparing acompound as claimed in claim 1, the process comprising reacting acompound of formula (II):

wherein X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R³², m and n are as definedin claim 1, with a compound of formula (IIIa):L¹-CO—Y—R⁹  (IIIa) wherein R⁹ is as defined in claim 1 and L¹ is aleaving group in the presence of a base, optionally in the presence of acoupling agent.
 6. A composition comprising a compound of formula (I),or a pharmaceutically acceptable salt thereof, as claimed in claim 1,and a pharmaceutically acceptable adjuvant, diluent or carrier thereof.7. A method of treating obstructive disease of airways a in a mammalsuffering from, or at risk of, said disease, which comprisesadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt, salt thereof, as claimed in claim
 1. 8. A methodaccording to claim 7, wherein the obstructive disease of airways isselected from the group consisting of chronic obstructive pulmonarydisease (COPD); asthma; bronchitis; acute, allergic, atrophic, orchronic rhinitis; membranous rhinitis; seasonal rhinitis; sarcoidosis;farmer's lung and related diseases; nasal polyposis; fibroid lung;idiopathic interstitial pneumonia; antitussive activity; chronic coughassociated with inflammatory conditions of the airways; and iatrogrenicinduced cough.
 9. A method according to claim 8, wherein the acute,allergic, atrophic, or chronic rhinitis is rhinitis caseoa, hypertrophicrhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa.10. A method according to claim 8, wherein the membranous rhinitis iscroupous, fibrinous or pseudomembranous rhinitis or scrofulous rhinitis.11. A method according to claim 8, wherein the seasonal rhinitisincluding rhinitis nervosa (hay fever) or vasomotor rhinitis.
 12. Amethod according to claim 7, wherein the obstructive disease of airwaysis asthma.
 13. A method according to claim 7, wherein the obstructivedisease of airways is rhinitis.
 14. A method of treating a disease orcondition selected from psoriasis, atopic dermatitis, contact dermatitisor other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus,Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria,angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis,Alopecia greata, and vernal conjunctivitis a in a mammal suffering from,or at risk of, said disease, which comprises administering to a mammalin need of such treatment a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt thereof,as claimed in claim 1.